Publications

@article{pmid38449289b,

title = {EpiVar browser: advanced exploration of epigenomics data under controlled access},

author = {David R Lougheed and Hanshi Liu and Katherine A Aracena and Romain Grégoire and Alain Pacis and Tomi Pastinen and Luis B Barreiro and Yann Joly and David Bujold and Guillaume Bourque},

doi = {10.1093/bioinformatics/btae136},

issn = {1367-4811},

year  = {2024},

date = {2024-03-01},

journal = {Bioinformatics},

abstract = {MOTIVATION: Human epigenomic data has been generated by large consortia for thousands of cell types to be used as a reference map of normal and disease chromatin states. Since epigenetic data contains potentially identifiable information, similarly to genetic data, most raw files generated by these consortia are stored in controlled-access databases. It is important to protect identifiable information, but this should not hinder secure sharing of these valuable datasets.



RESULTS: Guided by the Framework for responsible sharing of genomic and health-related data from the Global Alliance for Genomics and Health (GA4GH), we have developed an approach and a tool to facilitate the exploration of epigenomics datasets' aggregate results, while filtering out identifiable information. Specifically, the EpiVar Browser allows a user to navigate an epigenetic dataset from a cohort of individuals and enables direct exploration of genotype-chromatin phenotype relationships. Because individual genotypes and epigenetic signal tracks are not directly accessible, and rather aggregated in the portal output, no identifiable data is released, yet the interface allows for dynamic genotype-epigenome interrogation. This approach has the potential to accelerate analyses that would otherwise require a lengthy multi-step approval process and provides a generalisable strategy to facilitate responsible access to sensitive epigenomics data.



AVAILABILITY: Online portal: https://computationalgenomics.ca/tools/epivar; EpiVar Browser source code: https://github.com/c3g/epivar-browser; bw-merge-window tool source code: https://github.com/c3g/bw-merge-window.



SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38326393b,

title = {A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome},

author = {Claude Bhérer and Robert Eveleigh and Katerina Trajanoska and Janick St-Cyr and Antoine Paccard and Praveen Nadukkalam Ravindran and Elizabeth Caron and Nimara Bader Asbah and Peyton McClelland and Clare Wei and Iris Baumgartner and Marc Schindewolf and Yvonne Döring and Danielle Perley and François Lefebvre and Pierre Lepage and Mathieu Bourgey and Guillaume Bourque and Jiannis Ragoussis and Vincent Mooser and Daniel Taliun},

doi = {10.1038/s41525-024-00390-3},

issn = {2056-7944},

year  = {2024},

date = {2024-02-01},

journal = {NPJ Genom Med},

volume = {9},

number = {1},

pages = {8},

abstract = {Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a cost-effective method which we call "Whole Exome Genome Sequencing" (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38424460c,

title = {Epigenetic variation impacts individual differences in the transcriptional response to influenza infection},

author = {Katherine A Aracena and Yen-Lung Lin and Kaixuan Luo and Alain Pacis and Saideep Gona and Zepeng Mu and Vania Yotova and Renata Sindeaux and Albena Pramatarova and Marie-Michelle Simon and Xun Chen and Cristian Groza and David Lougheed and Romain Gregoire and David Brownlee and Carly Boye and Roger Pique-Regi and Yang Li and Xin He and David Bujold and Tomi Pastinen and Guillaume Bourque and Luis B Barreiro},

doi = {10.1038/s41588-024-01668-z},

issn = {1546-1718},

year  = {2024},

date = {2024-02-01},

journal = {Nat Genet},

abstract = {Humans display remarkable interindividual variation in their immune response to identical challenges. Yet, our understanding of the genetic and epigenetic factors contributing to such variation remains limited. Here we performed in-depth genetic, epigenetic and transcriptional profiling on primary macrophages derived from individuals of European and African ancestry before and after infection with influenza A virus. We show that baseline epigenetic profiles are strongly predictive of the transcriptional response to influenza A virus across individuals. Quantitative trait locus (QTL) mapping revealed highly coordinated genetic effects on gene regulation, with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. These data reveal that ancestry-associated differences in the epigenetic landscape can be genetically controlled, even more than gene expression. Lastly, among QTL variants that colocalized with immune-disease loci, only 7% were gene expression QTL, while the remaining genetic variants impact epigenetic marks, stressing the importance of considering molecular phenotypes beyond gene expression in disease-focused studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38253606b,

title = {Pangenome graphs improve the analysis of structural variants in rare genetic diseases},

author = {Cristian Groza and Carl Schwendinger-Schreck and Warren A Cheung and Emily G Farrow and Isabelle Thiffault and Juniper Lake and William B Rizzo and Gilad Evrony and Tom Curran and Guillaume Bourque and Tomi Pastinen},

doi = {10.1038/s41467-024-44980-2},

issn = {2041-1723},

year  = {2024},

date = {2024-01-01},

journal = {Nat Commun},

volume = {15},

number = {1},

pages = {657},

abstract = {Rare DNA alterations that cause heritable diseases are only partially resolvable by clinical next-generation sequencing due to the difficulty of detecting structural variation (SV) in all genomic contexts. Long-read, high fidelity genome sequencing (HiFi-GS) detects SVs with increased sensitivity and enables assembling personal and graph genomes. We leverage standard reference genomes, public assemblies (n = 94) and a large collection of HiFi-GS data from a rare disease program (Genomic Answers for Kids, GA4K, n = 574 assemblies) to build a graph genome representing a unified SV callset in GA4K, identify common variation and prioritize SVs that are more likely to cause genetic disease (MAF < 0.01). Using graphs, we obtain a higher level of reproducibility than the standard reference approach. We observe over 200,000 SV alleles unique to GA4K, including nearly 1000 rare variants that impact coding sequence. With improved specificity for rare SVs, we isolate 30 candidate SVs in phenotypically prioritized genes, including known disease SVs. We isolate a novel diagnostic SV in KMT2E, demonstrating use of personal assemblies coupled with pangenome graphs for rare disease genomics. The community may interrogate our pangenome with additional assemblies to discover new SVs within the allele frequency spectrum relevant to genetic diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38338754c,

title = {CircRNAome of Childhood Acute Lymphoblastic Leukemia: Deciphering Subtype-Specific Expression Profiles and Involvement in  ALL},

author = {Angela Gutierrez-Camino and Maxime Caron and Chantal Richer and Claire Fuchs and Unai Illarregi and Lucas Poncelet and Pascal St-Onge and Alain R Bataille and Pascal Tremblay-Dauphinais and Elixabet Lopez-Lopez and Mireia Camos and Manuel Ramirez-Orellana and Itziar Astigarraga and Éric Lécuyer and Guillaume Bourque and Idoia Martin-Guerrero and Daniel Sinnett},

doi = {10.3390/ijms25031477},

issn = {1422-0067},

year  = {2024},

date = {2024-01-01},

journal = {Int J Mol Sci},

volume = {25},

number = {3},

abstract = {Childhood B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous disease comprising multiple molecular subgroups with subtype-specific expression profiles. Recently, a new type of ncRNA, termed circular RNA (circRNA), has emerged as a promising biomarker in cancer, but little is known about their role in childhood B-ALL. Here, through RNA-seq analysis in 105 childhood B-ALL patients comprising six genetic subtypes and seven B-cell controls from two independent cohorts we demonstrated that circRNAs properly stratified B-ALL subtypes. By differential expression analysis of each subtype vs. controls, 156 overexpressed and 134 underexpressed circRNAs were identified consistently in at least one subtype, most of them with subtype-specific expression.  subtype was the one with the highest number of unique and overexpressed circRNAs, and the circRNA signature could effectively discriminate new patients with  subtype from others. Our results indicated that , an RNA-binding protein (RBP) involved in circRNA biogenesis, may contribute to this circRNA enrichment in  ALL. Further functional characterization using the CRISPR-Cas13d system demonstrated that , overexpressed in  patients and regulated by , might be involved in leukemogenesis through the activation of p38 via . Our results suggest that circRNAs could play a role in the pathogenesis of childhood B-ALL.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37395395b,

title = {ZMYM2 is essential for methylation of germline genes and active transposons in embryonic development},

author = {Adda-Lee Graham-Paquin and Deepak Saini and Jacinthe Sirois and Ishtiaque Hossain and Megan S Katz and Qinwei Kim-Wee Zhuang and Sin Young Kwon and Yojiro Yamanaka and Guillaume Bourque and Maxime Bouchard and William A Pastor},

doi = {10.1093/nar/gkad540},

issn = {1362-4962},

year  = {2023},

date = {2023-08-01},

journal = {Nucleic Acids Res},

volume = {51},

number = {14},

pages = {7314--7329},

abstract = {ZMYM2 is a transcriptional repressor whose role in development is largely unexplored. We found that Zmym2-/- mice show embryonic lethality by E10.5. Molecular characterization of Zmym2-/- embryos revealed two distinct defects. First, they fail to undergo DNA methylation and silencing of germline gene promoters, resulting in widespread upregulation of germline genes. Second, they fail to methylate and silence the evolutionarily youngest and most active LINE element subclasses in mice. Zmym2-/- embryos show ubiquitous overexpression of LINE-1 protein as well as aberrant expression of transposon-gene fusion transcripts. ZMYM2 homes to sites of PRC1.6 and TRIM28 complex binding, mediating repression of germline genes and transposons respectively. In the absence of ZMYM2, hypermethylation of histone 3 lysine 4 occurs at target sites, creating a chromatin landscape unfavourable for establishment of DNA methylation. ZMYM2-/- human embryonic stem cells also show aberrant upregulation and demethylation of young LINE elements, indicating a conserved role in repression of active transposons. ZMYM2 is thus an important new factor in DNA methylation patterning in early embryonic development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37599818b,

title = {Selection for immune evasion in SARS-CoV-2 revealed by high-resolution epitope mapping and sequence analysis},

author = {Arnaud N'Guessan and Senthilkumar Kailasam and Fatima Mostefai and Raphaël Poujol and Jean-Christophe Grenier and Nailya Ismailova and Paola Contini and Raffaele De Palma and Carsten Haber and Volker Stadler and Guillaume Bourque and Julie G Hussin and B Jesse Shapiro and Jörg H Fritz and Ciriaco A Piccirillo},

doi = {10.1016/j.isci.2023.107394},

issn = {2589-0042},

year  = {2023},

date = {2023-08-01},

journal = {iScience},

volume = {26},

number = {8},

pages = {107394},

abstract = {Here, we exploit a deep serological profiling strategy coupled with an integrated, computational framework for the analysis of SARS-CoV-2 humoral immune responses. Applying a high-density peptide array (HDPA) spanning the entire proteomes of SARS-CoV-2 and endemic human coronaviruses allowed identification of B cell epitopes and relate them to their evolutionary and structural properties. We identify hotspots of pre-existing immunity and identify cross-reactive epitopes that contribute to increasing the overall humoral immune response to SARS-CoV-2. Using a public dataset of over 38,000 viral genomes from the early phase of the pandemic, capturing both inter- and within-host genetic viral diversity, we determined the evolutionary profile of epitopes and the differences across proteins, waves, and SARS-CoV-2 variants. Lastly, we show that mutations in spike and nucleocapsid epitopes are under stronger selection between than within patients, suggesting that most of the selective pressure for immune evasion occurs upon transmission between hosts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37671027b,

title = {Pan-conserved segment tags identify ultra-conserved sequences across assemblies in the human pangenome},

author = {HoJoon Lee and Stephanie U Greer and Dmitri S Pavlichin and Bo Zhou and Alexander E Urban and Tsachy Weissman and  and Hanlee P Ji},

doi = {10.1016/j.crmeth.2023.100543},

issn = {2667-2375},

year  = {2023},

date = {2023-08-01},

journal = {Cell Rep Methods},

volume = {3},

number = {8},

pages = {100543},

abstract = {The human pangenome, a new reference sequence, addresses many limitations of the current GRCh38 reference. The first release is based on 94 high-quality haploid assemblies from individuals with diverse backgrounds. We employed a k-mer indexing strategy for comparative analysis across multiple assemblies, including the pangenome reference, GRCh38, and CHM13, a telomere-to-telomere reference assembly. Our k-mer indexing approach enabled us to identify a valuable collection of universally conserved sequences across all assemblies, referred to as "pan-conserved segment tags" (PSTs). By examining intervals between these segments, we discerned highly conserved genomic segments and those with structurally related polymorphisms. We found 60,764 polymorphic intervals with unique geo-ethnic features in the pangenome reference. In this study, we utilized ultra-conserved sequences (PSTs) to forge a link between human pangenome assemblies and reference genomes. This methodology enables the examination of any sequence of interest within the pangenome, using the reference genome as a comparative framework.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37165083b,

title = {Pangenome graph construction from genome alignments with Minigraph-Cactus},

author = {Glenn Hickey and Jean Monlong and Jana Ebler and Adam M Novak and Jordan M Eizenga and Yan Gao and  and Tobias Marschall and Heng Li and Benedict Paten},

doi = {10.1038/s41587-023-01793-w},

issn = {1546-1696},

year  = {2023},

date = {2023-05-01},

journal = {Nat Biotechnol},

abstract = {Pangenome references address biases of reference genomes by storing a representative set of diverse haplotypes and their alignment, usually as a graph. Alternate alleles determined by variant callers can be used to construct pangenome graphs, but advances in long-read sequencing are leading to widely available, high-quality phased assemblies. Constructing a pangenome graph directly from assemblies, as opposed to variant calls, leverages the graph's ability to represent variation at different scales. Here we present the Minigraph-Cactus pangenome pipeline, which creates pangenomes directly from whole-genome alignments, and demonstrate its ability to scale to 90 human haplotypes from the Human Pangenome Reference Consortium. The method builds graphs containing all forms of genetic variation while allowing use of current mapping and genotyping tools. We measure the effect of the quality and completeness of reference genomes used for analysis within the pangenomes and show that using the CHM13 reference from the Telomere-to-Telomere Consortium improves the accuracy of our methods. We also demonstrate construction of a Drosophila melanogaster pangenome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37165237b,

title = {Increased mutation and gene conversion within human segmental duplications},

author = {Mitchell R Vollger and Philip C Dishuck and William T Harvey and William S DeWitt and Xavi Guitart and Michael E Goldberg and Allison N Rozanski and Julian Lucas and Mobin Asri and  and Katherine M Munson and Alexandra P Lewis and Kendra Hoekzema and Glennis A Logsdon and David Porubsky and Benedict Paten and Kelley Harris and PingHsun Hsieh and Evan E Eichler},

doi = {10.1038/s41586-023-05895-y},

issn = {1476-4687},

year  = {2023},

date = {2023-05-01},

journal = {Nature},

volume = {617},

number = {7960},

pages = {325--334},

abstract = {Single-nucleotide variants (SNVs) in segmental duplications (SDs) have not been systematically assessed because of the limitations of mapping short-read sequencing data. Here we constructed 1:1 unambiguous alignments spanning high-identity SDs across 102 human haplotypes and compared the pattern of SNVs between unique and duplicated regions. We find that human SNVs are elevated 60% in SDs compared to unique regions and estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with up to 4.3 megabase pairs of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of about 800 protein-coding genes. These include 171 genes that have 'relocated' on average 1.61 megabase pairs in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are slightly evolutionarily older when compared to unique sequences, probably owing to IGC. SNVs in SDs, however, show a distinct mutational spectrum: a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts and a 7.6% reduction in the frequency of CpG-associated mutations when compared to unique DNA. We reason that these distinct mutational properties help to maintain an overall higher GC content of SD DNA compared to that of unique DNA, probably driven by GC-biased conversion between paralogous sequences.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37165241b,

title = {Recombination between heterologous human acrocentric chromosomes},

author = {Andrea Guarracino and Silvia Buonaiuto and Leonardo Gomes de Lima and Tamara Potapova and Arang Rhie and Sergey Koren and Boris Rubinstein and Christian Fischer and  and Jennifer L Gerton and Adam M Phillippy and Vincenza Colonna and Erik Garrison},

doi = {10.1038/s41586-023-05976-y},

issn = {1476-4687},

year  = {2023},

date = {2023-05-01},

journal = {Nature},

volume = {617},

number = {7960},

pages = {335--343},

abstract = {The short arms of the human acrocentric chromosomes 13, 14, 15, 21 and 22 (SAACs) share large homologous regions, including ribosomal DNA repeats and extended segmental duplications. Although the resolution of these regions in the first complete assembly of a human genome-the Telomere-to-Telomere Consortium's CHM13 assembly (T2T-CHM13)-provided a model of their homology, it remained unclear whether these patterns were ancestral or maintained by ongoing recombination exchange. Here we show that acrocentric chromosomes contain pseudo-homologous regions (PHRs) indicative of recombination between non-homologous sequences. Utilizing an all-to-all comparison of the human pangenome from the Human Pangenome Reference Consortium (HPRC), we find that contigs from all of the SAACs form a community. A variation graph constructed from centromere-spanning acrocentric contigs indicates the presence of regions in which most contigs appear nearly identical between heterologous acrocentric chromosomes in T2T-CHM13. Except on chromosome 15, we observe faster decay of linkage disequilibrium in the pseudo-homologous regions than in the corresponding short and long arms, indicating higher rates of recombination. The pseudo-homologous regions include sequences that have previously been shown to lie at the breakpoint of Robertsonian translocations, and their arrangement is compatible with crossover in inverted duplications on chromosomes 13, 14 and 21. The ubiquity of signals of recombination between heterologous acrocentric chromosomes seen in the HPRC draft pangenome suggests that these shared sequences form the basis for recurrent Robertsonian translocations, providing sequence and population-based confirmation of hypotheses first developed from cytogenetic studies 50 years ago.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37165242b,

title = {A draft human pangenome reference},

author = {Wen-Wei Liao and Mobin Asri and Jana Ebler and Daniel Doerr and Marina Haukness and Glenn Hickey and Shuangjia Lu and Julian K Lucas and Jean Monlong and Haley J Abel and Silvia Buonaiuto and Xian H Chang and Haoyu Cheng and Justin Chu and Vincenza Colonna and Jordan M Eizenga and Xiaowen Feng and Christian Fischer and Robert S Fulton and Shilpa Garg and Cristian Groza and Andrea Guarracino and William T Harvey and Simon Heumos and Kerstin Howe and Miten Jain and Tsung-Yu Lu and Charles Markello and Fergal J Martin and Matthew W Mitchell and Katherine M Munson and Moses Njagi Mwaniki and Adam M Novak and Hugh E Olsen and Trevor Pesout and David Porubsky and Pjotr Prins and Jonas A Sibbesen and Jouni Sirén and Chad Tomlinson and Flavia Villani and Mitchell R Vollger and Lucinda L Antonacci-Fulton and Gunjan Baid and Carl A Baker and Anastasiya Belyaeva and Konstantinos Billis and Andrew Carroll and Pi-Chuan Chang and Sarah Cody and Daniel E Cook and Robert M Cook-Deegan and Omar E Cornejo and Mark Diekhans and Peter Ebert and Susan Fairley and Olivier Fedrigo and Adam L Felsenfeld and Giulio Formenti and Adam Frankish and Yan Gao and Nanibaa' A Garrison and Carlos Garcia Giron and Richard E Green and Leanne Haggerty and Kendra Hoekzema and Thibaut Hourlier and Hanlee P Ji and Eimear E Kenny and Barbara A Koenig and Alexey Kolesnikov and Jan O Korbel and Jennifer Kordosky and Sergey Koren and HoJoon Lee and Alexandra P Lewis and Hugo Magalhães and Santiago Marco-Sola and Pierre Marijon and Ann McCartney and Jennifer McDaniel and Jacquelyn Mountcastle and Maria Nattestad and Sergey Nurk and Nathan D Olson and Alice B Popejoy and Daniela Puiu and Mikko Rautiainen and Allison A Regier and Arang Rhie and Samuel Sacco and Ashley D Sanders and Valerie A Schneider and Baergen I Schultz and Kishwar Shafin and Michael W Smith and Heidi J Sofia and Ahmad N Abou Tayoun and Françoise Thibaud-Nissen and Francesca Floriana Tricomi and Justin Wagner and Brian Walenz and Jonathan M D Wood and Aleksey V Zimin and Guillaume Bourque and Mark J P Chaisson and Paul Flicek and Adam M Phillippy and Justin M Zook and Evan E Eichler and David Haussler and Ting Wang and Erich D Jarvis and Karen H Miga and Erik Garrison and Tobias Marschall and Ira M Hall and Heng Li and Benedict Paten},

doi = {10.1038/s41586-023-05896-x},

issn = {1476-4687},

year  = {2023},

date = {2023-05-01},

journal = {Nature},

volume = {617},

number = {7960},

pages = {312--324},

abstract = {Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37170172b,

title = {Capturing sex-specific and hypofertility-linked effects of assisted reproductive technologies on the cord blood DNA methylome},

author = {Sophia Rahimi and Xiaojian Shao and Donovan Chan and Josée Martel and Anick Bérard and William D Fraser and Marie-Michelle Simon and Tony Kwan and Guillaume Bourque and Jacquetta Trasler},

doi = {10.1186/s13148-023-01497-7},

issn = {1868-7083},

year  = {2023},

date = {2023-05-01},

journal = {Clin Epigenetics},

volume = {15},

number = {1},

pages = {82},

abstract = {BACKGROUND: Children conceived through assisted reproduction are at an increased risk for growth and genomic imprinting disorders, often linked to DNA methylation defects. It has been suggested that assisted reproductive technology (ART) and underlying parental infertility can induce epigenetic instability, specifically interfering with DNA methylation reprogramming events during germ cell and preimplantation development. To date, human studies exploring the association between ART and DNA methylation defects have reported inconsistent or inconclusive results, likely due to population heterogeneity and the use of technologies with limited coverage of the epigenome. In our study, we explored the epigenetic risk of ART by comprehensively profiling the DNA methylome of 73 human cord blood samples of singleton pregnancies (n = 36 control group, n = 37 ART/hypofertile group) from a human prospective longitudinal birth cohort, the 3D (Design, Develop, Discover) Study, using a high-resolution sequencing-based custom capture panel that examines over 2.4 million autosomal CpGs in the genome.



RESULTS: We identified evidence of sex-specific effects of ART/hypofertility on cord blood DNA methylation patterns. Our genome-wide analyses identified ~ 46% more CpGs affected by ART/hypofertility in female than in male infant cord blood. We performed a detailed analysis of three imprinted genes which have been associated with altered DNA methylation following ART (KCNQ1OT1, H19/IGF2 and GNAS) and found that female infant cord blood was associated with DNA hypomethylation. When compared to less invasive procedures such as intrauterine insemination, more invasive ARTs (in vitro fertilization, intracytoplasmic sperm injection, embryo culture) resulted in more marked and distinct effects on the cord blood DNA methylome. In the in vitro group, we found a close to fourfold higher proportion of significantly enriched Gene Ontology terms involved in development than in the in vivo group.



CONCLUSIONS: Our study highlights the ability of a sensitive, targeted, sequencing-based approach to uncover DNA methylation perturbations in cord blood associated with hypofertility and ART and influenced by offspring sex and ART technique invasiveness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37228750b,

title = {Genome graphs detect human polymorphisms in active epigenomic state during influenza infection},

author = {Cristian Groza and Xun Chen and Alain Pacis and Marie-Michelle Simon and Albena Pramatarova and Katherine A Aracena and Tomi Pastinen and Luis B Barreiro and Guillaume Bourque},

doi = {10.1016/j.xgen.2023.100294},

issn = {2666-979X},

year  = {2023},

date = {2023-05-01},

journal = {Cell Genom},

volume = {3},

number = {5},

pages = {100294},

abstract = {Genetic variants, including mobile element insertions (MEIs), are known to impact the epigenome. We hypothesized that genome graphs, which encapsulate genetic diversity, could reveal missing epigenomic signals. To test this, we sequenced the epigenome of monocyte-derived macrophages from 35 ancestrally diverse individuals before and after influenza infection, allowing us to investigate the role of MEIs in immunity. We characterized genetic variants and MEIs using linked reads and built a genome graph. Mapping epigenetic data revealed 2.3%-3% novel peaks for H3K4me1, H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq), and ATAC-seq. Additionally, the use of a genome graph modified some quantitative trait loci estimates and revealed 375 polymorphic MEIs in an active epigenomic state. Among these is an AluYh3 polymorphism whose chromatin state changed after infection and was associated with the expression of , a gene that restricts influenza RNA synthesis. Our results demonstrate that graph genomes can reveal regulatory regions that would have been overlooked by other approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37228757b,

title = {Transposable elements are associated with the variable response to influenza infection},

author = {Xun Chen and Alain Pacis and Katherine A Aracena and Saideep Gona and Tony Kwan and Cristian Groza and Yen Lung Lin and Renata Sindeaux and Vania Yotova and Albena Pramatarova and Marie-Michelle Simon and Tomi Pastinen and Luis B Barreiro and Guillaume Bourque},

doi = {10.1016/j.xgen.2023.100292},

issn = {2666-979X},

year  = {2023},

date = {2023-05-01},

journal = {Cell Genom},

volume = {3},

number = {5},

pages = {100292},

abstract = {Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factors in variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36815791b,

title = {Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma},

author = {Naveen S Vasudev and Ghislaine Scelo and Kate I Glennon and Michelle Wilson and Louis Letourneau and Robert Eveleigh and Nazanin Nourbehesht and Madeleine Arseneault and Antoine Paccard and Lars Egevad and Juris Viksna and Edgars Celms and Sharon M Jackson and Behnoush Abedi-Ardekani and Anne Y Warren and Peter J Selby and Sebastian Trainor and Michael Kimuli and Jon Cartledge and Naeem Soomro and Adebanji Adeyoju and Poulam M Patel and Magdalena B Wozniak and Ivana Holcatova and Antonin Brisuda and Vladimir Janout and Estelle Chanudet and David Zaridze and Anush Moukeria and Oxana Shangina and Lenka Foretova and Marie Navratilova and Dana Mates and Viorel Jinga and Ljiljana Bogdanovic and Bozidar Kovacevic and Anne Cambon-Thomsen and Guillaume Bourque and Alvis Brazma and Jörg Tost and Paul Brennan and Mark Lathrop and Yasser Riazalhosseini and Rosamonde E Banks},

doi = {10.1158/1078-0432.CCR-22-1936},

issn = {1557-3265},

year  = {2023},

date = {2023-04-01},

journal = {Clin Cancer Res},

volume = {29},

number = {7},

pages = {1220--1231},

abstract = {PURPOSE: Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing.



EXPERIMENTAL DESIGN: The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework.



RESULTS: Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy.



CONCLUSIONS: Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36897015b,

title = {RNAget: an API to securely retrieve RNA quantifications},

author = {Sean Upchurch and Emilio Palumbo and Jeremy Adams and David Bujold and Guillaume Bourque and Jared Nedzel and Keenan Graham and Meenakshi S Kagda and Pedro Assis and Benjamin Hitz and Emilio Righi and Roderic Guigó and Barbara J Wold and },

doi = {10.1093/bioinformatics/btad126},

issn = {1367-4811},

year  = {2023},

date = {2023-04-01},

journal = {Bioinformatics},

volume = {39},

number = {4},

abstract = {SUMMARY: Large-scale sharing of genomic quantification data requires standardized access interfaces. In this Global Alliance for Genomics and Health project, we developed RNAget, an API for secure access to genomic quantification data in matrix form. RNAget provides for slicing matrices to extract desired subsets of data and is applicable to all expression matrix-format data, including RNA sequencing and microarrays. Further, it generalizes to quantification matrices of other sequence-based genomics such as ATAC-seq and ChIP-seq.



AVAILABILITY AND IMPLEMENTATION: https://ga4gh-rnaseq.github.io/schema/docs/index.html.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37069360b,

title = {Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease},

author = {Marie-Gabrielle Duperron and Maria J Knol and Quentin Le Grand and Tavia E Evans and Aniket Mishra and Ami Tsuchida and Gennady Roshchupkin and Takahiro Konuma and David-Alexandre Trégouët and Jose Rafael Romero and Stefan Frenzel and Michelle Luciano and Edith Hofer and Mathieu Bourgey and Nicole D Dueker and Pilar Delgado and Saima Hilal and Rick M Tankard and Florian Dubost and Jean Shin and Yasaman Saba and Nicola J Armstrong and Constance Bordes and Mark E Bastin and Alexa Beiser and Henry Brodaty and Robin Bülow and Caty Carrera and Christopher Chen and Ching-Yu Cheng and Ian J Deary and Piyush G Gampawar and Jayandra J Himali and Jiyang Jiang and Takahisa Kawaguchi and Shuo Li and Melissa Macalli and Pascale Marquis and Zoe Morris and Susana Muñoz Maniega and Susumu Miyamoto and Masakazu Okawa and Matthew Paradise and Pedram Parva and Tatjana Rundek and Muralidharan Sargurupremraj and Sabrina Schilling and Kazuya Setoh and Omar Soukarieh and Yasuharu Tabara and Alexander Teumer and Anbupalam Thalamuthu and Julian N Trollor and Maria C Valdés Hernández and Meike W Vernooij and Uwe Völker and Katharina Wittfeld and Tien Yin Wong and Margaret J Wright and Junyi Zhang and Wanting Zhao and Yi-Cheng Zhu and Helena Schmidt and Perminder S Sachdev and Wei Wen and Kazumichi Yoshida and Anne Joutel and Claudia L Satizabal and Ralph L Sacco and Guillaume Bourque and  and Mark Lathrop and Tomas Paus and Israel Fernandez-Cadenas and Qiong Yang and Bernard Mazoyer and Philippe Boutinaud and Yukinori Okada and Hans J Grabe and Karen A Mather and Reinhold Schmidt and Marc Joliot and M Arfan Ikram and Fumihiko Matsuda and Christophe Tzourio and Joanna M Wardlaw and Sudha Seshadri and Hieab H H Adams and Stéphanie Debette},

doi = {10.1038/s41591-023-02268-w},

issn = {1546-170X},

year  = {2023},

date = {2023-04-01},

journal = {Nat Med},

volume = {29},

number = {4},

pages = {950--962},

abstract = {Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37164484b,

title = {Gaps and complex structurally variant loci in phased genome assemblies},

author = {David Porubsky and Mitchell R Vollger and William T Harvey and Allison N Rozanski and Peter Ebert and Glenn Hickey and Patrick Hasenfeld and Ashley D Sanders and Catherine Stober and  and Jan O Korbel and Benedict Paten and Tobias Marschall and Evan E Eichler},

doi = {10.1101/gr.277334.122},

issn = {1549-5469},

year  = {2023},

date = {2023-04-01},

journal = {Genome Res},

volume = {33},

number = {4},

pages = {496--510},

abstract = {There has been tremendous progress in phased genome assembly production by combining long-read data with parental information or linked-read data. Nevertheless, a typical phased genome assembly generated by trio-hifiasm still generates more than 140 gaps. We perform a detailed analysis of gaps, assembly breaks, and misorientations from 182 haploid assemblies obtained from a diversity panel of 77 unique human samples. Although trio-based approaches using HiFi are the current gold standard, chromosome-wide phasing accuracy is comparable when using Strand-seq instead of parental data. Importantly, the majority of assembly gaps cluster near the largest and most identical repeats (including segmental duplications [35.4%], satellite DNA [22.3%], or regions enriched in GA/AT-rich DNA [27.4%]). Consequently, 1513 protein-coding genes overlap assembly gaps in at least one haplotype, and 231 are recurrently disrupted or missing from five or more haplotypes. Furthermore, we estimate that 6-7 Mbp of DNA are misorientated per haplotype irrespective of whether trio-free or trio-based approaches are used. Of these misorientations, 81% correspond to bona fide large inversion polymorphisms in the human species, most of which are flanked by large segmental duplications. We also identify large-scale alignment discontinuities consistent with 11.9 Mbp of deletions and 161.4 Mbp of insertions per haploid genome. Although 99% of this variation corresponds to satellite DNA, we identify 230 regions of euchromatic DNA with frequent expansions and contractions, nearly half of which overlap with 197 protein-coding genes. Such variable and incompletely assembled regions are important targets for future algorithmic development and pangenome representation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36454369b,

title = {Genetic variation in the Y chromosome and sex-biased DNA methylation in somatic cells in the mouse},

author = {Enkhjin Batdorj and Najla AlOgayil and Qinwei Kim-Wee Zhuang and Jose Hector Galvez and Klara Bauermeister and Kei Nagata and Tohru Kimura and Monika A Ward and Teruko Taketo and Guillaume Bourque and Anna K Naumova},

doi = {10.1007/s00335-022-09970-z},

issn = {1432-1777},

year  = {2023},

date = {2023-03-01},

journal = {Mamm Genome},

volume = {34},

number = {1},

pages = {44--55},

abstract = {Several lines of evidence suggest that the presence of the Y chromosome influences DNA methylation of autosomal loci. To better understand the impact of the Y chromosome on autosomal DNA methylation patterns and its contribution to sex bias in methylation, we identified Y chromosome dependent differentially methylated regions (yDMRs) using whole-genome bisulfite sequencing methylation data from livers of mice with different combinations of sex-chromosome complement and gonadal sex. Nearly 90% of the autosomal yDMRs mapped to transposable elements (TEs) and most of them had lower methylation in XY compared to XX or XO mice. Follow-up analyses of four reporter autosomal yDMRs showed that Y-dependent methylation levels were consistent across most somatic tissues but varied in strains with different origins of the Y chromosome, suggesting that genetic variation in the Y chromosome influenced methylation levels of autosomal regions. Mice lacking the q-arm of the Y chromosome (B6.NPYq-2) as well as mice with a loss-of-function mutation in Kdm5d showed no differences in methylation levels compared to wild type mice. In conclusion, the Y-linked modifier of TE methylation is likely to reside on the short arm of Y chromosome and further studies are required to identify this gene.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36449158b,

title = {Genotyping of Transposable Element Insertions Segregating in Human Populations Using Short-Read Realignments},

author = {Xun Chen and Guillaume Bourque and Clément Goubert},

doi = {10.1007/978-1-0716-2883-6_4},

issn = {1940-6029},

year  = {2023},

date = {2023-01-01},

journal = {Methods Mol Biol},

volume = {2607},

pages = {63--83},

abstract = {Transposable element (TE) insertions are a major source of structural variation in the human genome. Due to the repetitive nature and biological importance of TEs, many bioinformatic tools have been developed to identify and genotype TE insertion polymorphisms using high-throughput short-reads. In this chapter, we outline recently developed methods to characterize TE insertion polymorphisms in human populations. We also provide detailed protocols to tackle this question primarily using three software: MELT2, ERVcaller, and TypeREF.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36449159b,

title = {A Pangenome Approach to Detect and Genotype TE Insertion Polymorphisms},

author = {Cristian Groza and Guillaume Bourque and Clément Goubert},

doi = {10.1007/978-1-0716-2883-6_5},

issn = {1940-6029},

year  = {2023},

date = {2023-01-01},

journal = {Methods Mol Biol},

volume = {2607},

pages = {85--94},

abstract = {Pangenome graphs are flexible data structures that contain the genetic variation that exists in a population of genomes and describe the sequences of the many possible ensuing haplotypes. Here, we use such a pangenome graph to represent and genotype transposable element (TE) polymorphisms. By combining the transposable element annotation (Alus, L1s, and SVAs) of the human genome reference with novel transposable element insertions observed in two high-quality assemblies (HG002 and HG00733), we show how to create a transposable element pangenome that consists of ~1.2 million reference and 2939 non-reference transposable elements. We then demonstrate this approach by aligning short-read sequencing data and genotyping transposable element deletions and insertions with reasonable specificity and sensitivity (0.85 F1-score).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37576549b,

title = {Glucocorticoid stimulation induces regionalized gene responses within topologically associating domains},

author = {Christophe Tav and Éric Fournier and Michèle Fournier and Fatemeh Khadangi and Audrey Baguette and Maxime C Côté and Maruhen A D Silveira and Félix-Antoine Bérubé-Simard and Guillaume Bourque and Arnaud Droit and Steve Bilodeau},

doi = {10.3389/fgene.2023.1237092},

issn = {1664-8021},

year  = {2023},

date = {2023-01-01},

journal = {Front Genet},

volume = {14},

pages = {1237092},

abstract = {Transcription-factor binding to cis-regulatory regions regulates the gene expression program of a cell, but occupancy is often a poor predictor of the gene response. Here, we show that glucocorticoid stimulation led to the reorganization of transcriptional coregulators MED1 and BRD4 within topologically associating domains (TADs), resulting in active or repressive gene environments. Indeed, we observed a bias toward the activation or repression of a TAD when their activities were defined by the number of regions gaining and losing MED1 and BRD4 following dexamethasone (Dex) stimulation. Variations in Dex-responsive genes at the RNA levels were consistent with the redistribution of MED1 and BRD4 at the associated cis-regulatory regions. Interestingly, Dex-responsive genes without the differential recruitment of MED1 and BRD4 or binding by the glucocorticoid receptor were found within TADs, which gained or lost MED1 and BRD4, suggesting a role of the surrounding environment in gene regulation. However, the amplitude of the response of Dex-regulated genes was higher when the differential recruitment of the glucocorticoid receptor and transcriptional coregulators was observed, reaffirming the role of transcription factor-driven gene regulation and attributing a lesser role to the TAD environment. These results support a model where a signal-induced transcription factor induces a regionalized effect throughout the TAD, redefining the notion of direct and indirect effects of transcription factors on target genes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36611933b,

title = {Identification of R-Spondin Gene Signature Predictive of Metastatic Progression in BRAFV-Positive Papillary Thyroid Cancer},

author = {Sabrina Daniela da Silva and Grégoire B Morand and Luciana Diesel and Jefferson Muniz de Lima and Krikor Bijian and Senthilkumar Kailasam and Francois Lefebvre and Guillaume Bourque and Michael Hier and Moulay A Alaoui-Jamali},

doi = {10.3390/cells12010139},

issn = {2073-4409},

year  = {2022},

date = {2022-12-01},

journal = {Cells},

volume = {12},

number = {1},

abstract = {Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland and early stages are curable. However, a subset of PTCs shows an unusually aggressive phenotype with extensive lymph node metastasis and higher incidence of locoregional recurrence. In this study, we investigated a large cohort of PTC cases with an unusual aggressive phenotype using a high-throughput RNA sequencing (RNA-Seq) to identify differentially regulated genes associated with metastatic PTC. All metastatic PTC with mutated BRAF (V600E) but not BRAF wild-type expressed an up-regulation of R-Spondin Protein 4 (RSPO4) concomitant with an upregulation of genes involved in focal adhesion and cell-extracellular matrix signaling. Further immunohistochemistry validation confirmed the upregulation of these target genes in metastatic PTC cases. Preclinical studies using established PTC cell lines support that RSPO4 overexpression is associated with BRAF V600E mutation and is a critical upstream event that promote activation of kinases of focal adhesion signaling known to drive cancer cell locomotion and invasion. This finding opens up the potential of co-targeting B-Raf, RSPO and focal adhesion proteins as a pharmacological approach for aggressive BRAF V600E PTC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35416251b,

title = {Glioblastoma scRNA-seq shows treatment-induced, immune-dependent increase in mesenchymal cancer cells and structural variants in distal neural stem cells},

author = {Charles P Couturier and Javad Nadaf and Zhaorong Li and Salma Baig and Gabriele Riva and Phuong Le and Daan J Kloosterman and Jean Monlong and Andriniaina Nkili Meyong and Redouane Allache and Theresa Degenhard and Mariam Al-Rashid and Marie-Christine Guiot and Guillaume Bourque and Jiannis Ragoussis and Leila Akkari and Francisco J Quintana and Kevin Petrecca},

doi = {10.1093/neuonc/noac085},

issn = {1523-5866},

year  = {2022},

date = {2022-09-01},

journal = {Neuro Oncol},

volume = {24},

number = {9},

pages = {1494--1508},

abstract = {BACKGROUND: Glioblastoma is a treatment-resistant brain cancer. Its hierarchical cellular nature and its tumor microenvironment (TME) before, during, and after treatments remain unresolved.



METHODS: Here, we used single-cell RNA sequencing to analyze new and recurrent glioblastoma and the nearby subventricular zone (SVZ).



RESULTS: We found 4 glioblastoma neural lineages are present in new and recurrent glioblastoma with an enrichment of the cancer mesenchymal lineage, immune cells, and reactive astrocytes in early recurrences. Cancer lineages were hierarchically organized around cycling oligodendrocytic and astrocytic progenitors that are transcriptomically similar but distinct to SVZ neural stem cells (NSCs). Furthermore, NSCs from the SVZ of patients with glioblastoma harbored glioblastoma chromosomal anomalies. Lastly, mesenchymal cancer cells and TME reactive astrocytes shared similar gene signatures which were induced by radiotherapy in a myeloid-dependent fashion in vivo.



CONCLUSION: These data reveal the dynamic, immune-dependent nature of glioblastoma's response to treatments and identify distant NSCs as likely cells of origin.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35863436b,

title = {The amino acid sensor GCN2 suppresses terminal oligopyrimidine (TOP) mRNA translation via La-related protein 1 (LARP1)},

author = {Zeenat Farooq and Fedho Kusuma and Phillip Burke and Catherine R Dufour and Duckgue Lee and Negar Tabatabaei and Phoenix Toboz and Ernest Radovani and Jack F Greenblatt and Jalees Rehman and Jacob Class and Arkady Khoutorsky and Bruno D Fonseca and Justin M Richner and Eloi Mercier and Guillaume Bourque and Vincent Giguère and Arvind R Subramaniam and Jaeseok Han and Soroush Tahmasebi},

doi = {10.1016/j.jbc.2022.102277},

issn = {1083-351X},

year  = {2022},

date = {2022-09-01},

journal = {J Biol Chem},

volume = {298},

number = {9},

pages = {102277},

abstract = {La-related protein 1 (LARP1) has been identified as a key translational inhibitor of terminal oligopyrimidine (TOP) mRNAs downstream of the nutrient sensing protein kinase complex, mTORC1. LARP1 exerts this inhibitory effect on TOP mRNA translation by binding to the mRNA cap and the adjacent 5'TOP motif, resulting in the displacement of the cap-binding protein eIF4E from TOP mRNAs. However, the involvement of additional signaling pathway in regulating LARP1-mediated inhibition of TOP mRNA translation is largely unexplored. In the present study, we identify a second nutrient sensing kinase GCN2 that converges on LARP1 to control TOP mRNA translation. Using chromatin-immunoprecipitation followed by massive parallel sequencing (ChIP-seq) analysis of activating transcription factor 4 (ATF4), an effector of GCN2 in nutrient stress conditions, in WT and GCN2 KO mouse embryonic fibroblasts, we determined that LARP1 is a GCN2-dependent transcriptional target of ATF4. Moreover, we identified GCN1, a GCN2 activator, participates in a complex with LARP1 on stalled ribosomes, suggesting a role for GCN1 in LARP1-mediated translation inhibition in response to ribosome stalling. Therefore, our data suggest that the GCN2 pathway controls LARP1 activity via two mechanisms: ATF4-dependent transcriptional induction of LARP1 mRNA and GCN1-mediated recruitment of LARP1 to stalled ribosomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35648852b,

title = {A systems biology approach identifies candidate drugs to reduce mortality in severely ill patients with COVID-19},

author = {Vinicius M Fava and Mathieu Bourgey and Pubudu M Nawarathna and Marianna Orlova and Pauline Cassart and Donald C Vinh and Matthew Pellan Cheng and Guillaume Bourque and Erwin Schurr and David Langlais},

doi = {10.1126/sciadv.abm2510},

issn = {2375-2548},

year  = {2022},

date = {2022-06-01},

journal = {Sci Adv},

volume = {8},

number = {22},

pages = {eabm2510},

abstract = {Despite the availability of highly efficacious vaccines, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lacks effective drug treatment, which results in a high rate of mortality. To address this therapeutic shortcoming, we applied a systems biology approach to the study of patients hospitalized with severe COVID. We show that, at the time of hospital admission, patients who were equivalent on the clinical ordinal scale displayed significant differential monocyte epigenetic and transcriptomic attributes between those who would survive and those who would succumb to COVID-19. We identified messenger RNA metabolism, RNA splicing, and interferon signaling pathways as key host responses overactivated by patients who would not survive. Those pathways are prime drug targets to reduce mortality of critically ill patients with COVID-19, leading us to identify tacrolimus, zotatifin, and nintedanib as three strong candidates for treatment of severely ill patients at the time of hospital admission.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36337358b,

title = {More than a 'Hundred Days War': Persistent SARS-CoV-2 infection in a patient with ANCA-associated vasculitis},

author = {Arielle Mendel and Ines Colmegna and Guillaume Bourque and Ewa Rajda and Todd C Lee and José Héctor Gálvez and Évelyne Vinet and Matthew P Cheng},

doi = {10.3138/jammi-2021-0033},

issn = {2371-0888},

year  = {2022},

date = {2022-06-01},

journal = {J Assoc Med Microbiol Infect Dis Can},

volume = {7},

number = {2},

pages = {131--134},

abstract = {BACKGROUND: Few reports exist on the characteristics and outcomes of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunocompromised hosts.



METHODS: A 49-year-old patient with granulomatosis with polyangiitis (GPA) and a renal transplant experienced multiple hospitalizations for coronavirus disease 2019 (COVID-19) pneumonia and relapses between October 2020 and February 2021. Careful chart review of medical history, hospitalizations, and microbiological testing including SARS-CoV-2 cycle threshold values, therapies, and imaging was undertaken. SARS-CoV-2 genome sequencing was performed in five viral samples to distinguish persistent infection from re-infection with a different strain.



RESULTS: Sequencing confirmed that all samples tested were from the same viral lineage, indicating a long-term, persistent infection rather than re-infection with a new strain. The patient ultimately stabilized after two courses of remdesivir plus dexamethasone, replacement intravenous immunoglobulin, and bamlanivimab. Rituximab maintenance therapy for vasculitis remains on hold.



CONCLUSIONS: SARS-CoV-2 may persist for several months in immunocompromised hosts and may go unrecognized as an ongoing active infection. More studies are needed to determine how to optimize COVID-19 treatment in this vulnerable population.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35720974b,

title = {PrecisionFDA Truth Challenge V2: Calling variants from short and long reads in difficult-to-map regions},

author = {Nathan D Olson and Justin Wagner and Jennifer McDaniel and Sarah H Stephens and Samuel T Westreich and Anish G Prasanna and Elaine Johanson and Emily Boja and Ezekiel J Maier and Omar Serang and David Jáspez and José M Lorenzo-Salazar and Adrián Muñoz-Barrera and Luis A Rubio-Rodríguez and Carlos Flores and Konstantinos Kyriakidis and Andigoni Malousi and Kishwar Shafin and Trevor Pesout and Miten Jain and Benedict Paten and Pi-Chuan Chang and Alexey Kolesnikov and Maria Nattestad and Gunjan Baid and Sidharth Goel and Howard Yang and Andrew Carroll and Robert Eveleigh and Mathieu Bourgey and Guillaume Bourque and Gen Li and ChouXian Ma and LinQi Tang and YuanPing Du and ShaoWei Zhang and Jordi Morata and Raúl Tonda and Genís Parra and Jean-Rémi Trotta and Christian Brueffer and Sinem Demirkaya-Budak and Duygu Kabakci-Zorlu and Deniz Turgut and Özem Kalay and Gungor Budak and Kübra Narcı and Elif Arslan and Richard Brown and Ivan J Johnson and Alexey Dolgoborodov and Vladimir Semenyuk and Amit Jain and H Serhat Tetikol and Varun Jain and Mike Ruehle and Bryan Lajoie and Cooper Roddey and Severine Catreux and Rami Mehio and Mian Umair Ahsan and Qian Liu and Kai Wang and Sayed Mohammad Ebrahim Sahraeian and Li Tai Fang and Marghoob Mohiyuddin and Calvin Hung and Chirag Jain and Hanying Feng and Zhipan Li and Luoqi Chen and Fritz J Sedlazeck and Justin M Zook},

doi = {10.1016/j.xgen.2022.100129},

issn = {2666-979X},

year  = {2022},

date = {2022-05-01},

journal = {Cell Genom},

volume = {2},

number = {5},

abstract = {The precisionFDA Truth Challenge V2 aimed to assess the state of the art of variant calling in challenging genomic regions. Starting with FASTQs, 20 challenge participants applied their variant-calling pipelines and submitted 64 variant call sets for one or more sequencing technologies (Illumina, PacBio HiFi, and Oxford Nanopore Technologies). Submissions were evaluated following best practices for benchmarking small variants with updated Genome in a Bottle benchmark sets and genome stratifications. Challenge submissions included numerous innovative methods, with graph-based and machine learning methods scoring best for short-read and long-read datasets, respectively. With machine learning approaches, combining multiple sequencing technologies performed particularly well. Recent developments in sequencing and variant calling have enabled benchmarking variants in challenging genomic regions, paving the way for the identification of previously unknown clinically relevant variants.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35188098b,

title = {Application of ATAC-Seq for genome-wide analysis of the chromatin state at single myofiber resolution},

author = {Korin Sahinyan and Darren M Blackburn and Marie-Michelle Simon and Felicia Lazure and Tony Kwan and Guillaume Bourque and Vahab D Soleimani},

doi = {10.7554/eLife.72792},

issn = {2050-084X},

year  = {2022},

date = {2022-02-01},

journal = {Elife},

volume = {11},

abstract = {Myofibers are the main components of skeletal muscle, which is the largest tissue in the body. Myofibers are highly adaptive and can be altered under different biological and disease conditions. Therefore, transcriptional and epigenetic studies on myofibers are crucial to discover how chromatin alterations occur in the skeletal muscle under different conditions. However, due to the heterogenous nature of skeletal muscle, studying myofibers in isolation proves to be a challenging task. Single-cell sequencing has permitted the study of the epigenome of isolated myonuclei. While this provides sequencing with high dimensionality, the sequencing depth is lacking, which makes comparisons between different biological conditions difficult. Here, we report the first implementation of single myofiber ATAC-Seq, which allows for the sequencing of an individual myofiber at a depth sufficient for peak calling and for comparative analysis of chromatin accessibility under various physiological and disease conditions. Application of this technique revealed significant differences in chromatin accessibility between resting and regenerating myofibers, as well as between myofibers from a mouse model of Duchenne Muscular Dystrophy (mdx) and wild-type (WT) counterparts. This technique can lead to a wide application in the identification of chromatin regulatory elements and epigenetic mechanisms in muscle fibers during development and in muscle-wasting diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34996498b,

title = {Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations},

author = {Charles E Breeze and Eric Haugen and Alex Reynolds and Andrew Teschendorff and Jenny van Dongen and Qing Lan and Nathaniel Rothman and Guillaume Bourque and Ian Dunham and Stephan Beck and John Stamatoyannopoulos and Nora Franceschini and Sonja I Berndt},

doi = {10.1186/s13059-021-02560-3},

issn = {1474-760X},

year  = {2022},

date = {2022-01-01},

journal = {Genome Biol},

volume = {23},

number = {1},

pages = {13},

abstract = {BACKGROUND: Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk.



RESULTS: To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 ( https://forge2.altiusinstitute.org/ ), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology.



CONCLUSION: In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35547873b,

title = {Intra-Tumoral CD8+ T-Cell Infiltration and PD-L1 Positivity in Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma},

author = {Bryn Golesworthy and Yifan Wang and Amanda Tanti and Alain Pacis and Joan Miguel Romero and Adeline Cuggia and Celine Domecq and Guillaume Bourdel and Robert E Denroche and Gun Ho Jang and Robert C Grant and Ayelet Borgida and Barbara T Grünwald and Anna Dodd and Julie M Wilson and Guillaume Bourque and Grainne M O'Kane and Sandra E Fischer and Chelsea Maedler Kron and Pierre-Olivier Fiset and Atilla Omeroglu and William D Foulkes and Steven Gallinger and Marie-Christine Guiot and Zu-Hua Gao and George Zogopoulos},

doi = {10.3389/fonc.2022.860767},

issn = {2234-943X},

year  = {2022},

date = {2022-01-01},

journal = {Front Oncol},

volume = {12},

pages = {860767},

abstract = {The immune contexture of pancreatic ductal adenocarcinoma (PDAC) is generally immunosuppressive. A role for immune checkpoint inhibitors (ICIs) in PDAC has only been demonstrated for the rare and hypermutated mismatch repair (MMR) deficient (MMR-d) subtype. Homologous recombination repair (HR) deficient (HR-d) PDAC is more prevalent and may encompass up to 20% of PDAC. Its genomic instability may promote a T-cell mediated anti-tumor response with therapeutic sensitivity to ICIs. To investigate the immunogenicity of HR-d PDAC, we used multiplex immunohistochemistry (IHC) to compare the density and spatial distribution of CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells (Tregs), and CD68+ tumor-associated macrophages (TAMs) in HR-d  HR/MMR-intact PDAC. We also evaluated the IHC positivity of programmed death-ligand 1 (PD-L1) across the subgroups. 192 tumors were evaluated and classified as HR/MMR-intact (n=166), HR-d (n=25) or MMR-d (n=1) based on germline testing and tumor molecular hallmarks. Intra-tumoral CD8+ T-cell infiltration was higher in HR-d  HR/MMR-intact PDAC (p<0.0001), while CD8+ T-cell densities in the peri-tumoral and stromal regions were similar in both groups. HR-d PDAC also displayed increased intra-tumoral FOXP3+ Tregs (p=0.049) and had a higher CD8+:FOXP3+ ratio (p=0.023). CD68+ TAM expression was similar in HR-d and HR/MMR-intact PDAC. Finally, 6 of the 25 HR-d cases showed a PD-L1 Combined Positive Score of >=1, whereas none of the HR/MMR-intact cases met this threshold (p<0.00001). These results provide immunohistochemical evidence for intra-tumoral CD8+ T-cell enrichment and PD-L1 positivity in HR-d PDAC, suggesting that HR-d PDAC may be amenable to ICI treatment strategies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34731633b,

title = {Inherent genomic properties underlie the epigenomic heterogeneity of human induced pluripotent stem cells},

author = {Shihori Yokobayashi and Yukihiro Yabuta and Masato Nakagawa and Keisuke Okita and Bo Hu and Yusuke Murase and Tomonori Nakamura and Guillaume Bourque and Jacek Majewski and Takuya Yamamoto and Mitinori Saitou},

doi = {10.1016/j.celrep.2021.109909},

issn = {2211-1247},

year  = {2021},

date = {2021-11-01},

journal = {Cell Rep},

volume = {37},

number = {5},

pages = {109909},

abstract = {Human induced pluripotent stem cells (hiPSCs) show variable differentiation potential due to their epigenomic heterogeneity, whose extent/attributes remain unclear, except for well-studied elements/chromosomes such as imprints and the X chromosomes. Here, we show that seven hiPSC lines with variable germline potential exhibit substantial epigenomic heterogeneity, despite their uniform transcriptomes. Nearly a quarter of autosomal regions bear potentially differential chromatin modifications, with promoters/CpG islands for H3K27me3/H2AK119ub1 and evolutionarily young retrotransposons for H3K4me3. We identify 145 large autosomal blocks (≥100 kb) with differential H3K9me3 enrichment, many of which are lamina-associated domains (LADs) in somatic but not in embryonic stem cells. A majority of these epigenomic heterogeneities are independent of genetic variations. We identify an X chromosome state with chromosome-wide H3K9me3 that stably prevents X chromosome erosion. Importantly, the germline potential of female hiPSCs correlates with X chromosome inactivation. We propose that inherent genomic properties, including CpG density, transposons, and LADs, engender epigenomic heterogeneity in hiPSCs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34706766b,

title = {A small number of early introductions seeded widespread transmission of SARS-CoV-2 in Québec, Canada},

author = {Carmen Lía Murall and Eric Fournier and Jose Hector Galvez and Arnaud N'Guessan and Sarah J Reiling and Pierre-Olivier Quirion and Sana Naderi and Anne-Marie Roy and Shu-Huang Chen and Paul Stretenowich and Mathieu Bourgey and David Bujold and Romain Gregoire and Pierre Lepage and Janick St-Cyr and Patrick Willet and Réjean Dion and Hugues Charest and Mark Lathrop and Michel Roger and Guillaume Bourque and Jiannis Ragoussis and B Jesse Shapiro and Sandrine Moreira},

doi = {10.1186/s13073-021-00986-9},

issn = {1756-994X},

year  = {2021},

date = {2021-10-01},

journal = {Genome Med},

volume = {13},

number = {1},

pages = {169},

abstract = {BACKGROUND: Québec was the Canadian province most impacted by COVID-19, with 401,462 cases as of September 24th, 2021, and 11,347 deaths due mostly to a very severe first pandemic wave. In April 2020, we assembled the Coronavirus Sequencing in Québec (CoVSeQ) consortium to sequence SARS-CoV-2 genomes in Québec to track viral introduction events and transmission within the province.



METHODS: Using genomic epidemiology, we investigated the arrival of SARS-CoV-2 to Québec. We report 2921 high-quality SARS-CoV-2 genomes in the context of > 12,000 publicly available genomes sampled globally over the first pandemic wave (up to June 1st, 2020). By combining phylogenetic and phylodynamic analyses with epidemiological data, we quantify the number of introduction events into Québec, identify their origins, and characterize the spatiotemporal spread of the virus.



RESULTS: Conservatively, we estimated approximately 600 independent introduction events, the majority of which happened from spring break until 2 weeks after the Canadian border closed for non-essential travel. Subsequent mass repatriations did not generate large transmission lineages (> 50 sequenced cases), likely due to mandatory quarantine measures in place at the time. Consistent with common spring break and "snowbird" destinations, most of the introductions were inferred to have originated from Europe via the Americas. Once introduced into Québec, viral lineage sizes were overdispersed, with a few lineages giving rise to most infections. Consistent with founder effects, the earliest lineages to arrive tended to spread most successfully. Fewer than 100 viral introductions arrived during spring break, of which 7-12 led to the largest transmission lineages of the first wave (accounting for 52-75% of all sequenced infections). These successful transmission lineages dispersed widely across the province. Transmission lineage size was greatly reduced after March 11th, when a quarantine order for returning travellers was enacted. While this suggests the effectiveness of early public health measures, the biggest transmission lineages had already been ignited prior to this order.



CONCLUSIONS: Combined, our results reinforce how, in the absence of tight travel restrictions or quarantine measures, fewer than 100 viral introductions in a week can ensure the establishment of extended transmission chains.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33433612b,

title = {Invasive growth associated with cold-inducible RNA-binding protein expression drives recurrence of surgically resected brain metastases},

author = {Matthew Dankner and Maxime Caron and Tariq Al-Saadi and WenQing Yu and Véronique Ouellet and Rima Ezzeddine and Sarah M Maritan and Matthew G Annis and Phuong Uyen Le and Javad Nadaf and Noah S Neubarth and Paul Savage and Dongmei Zuo and Charles P Couturier and Jean Monlong and Haig Djambazian and Huda Altoukhi and Guillaume Bourque and Jiannis Ragoussis and Roberto J Diaz and Morag Park and Marie-Christine Guiot and Stephanie Lam and Kevin Petrecca and Peter M Siegel},

doi = {10.1093/neuonc/noab002},

issn = {1523-5866},

year  = {2021},

date = {2021-09-01},

journal = {Neuro Oncol},

volume = {23},

number = {9},

pages = {1470--1480},

abstract = {BACKGROUND: Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival.



METHODS: We determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues.



RESULTS: We demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified cold-inducible RNA-binding protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain.



CONCLUSIONS: These data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying postoperative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected BrM.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34043590b,

title = {Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19},

author = {Gundula Povysil and Guillaume Butler-Laporte and Ning Shang and Chen Wang and Atlas Khan and Manal Alaamery and Tomoko Nakanishi and Sirui Zhou and Vincenzo Forgetta and Robert Jm Eveleigh and Mathieu Bourgey and Naveed Aziz and Steven Jm Jones and Bartha Knoppers and Stephen W Scherer and Lisa J Strug and Pierre Lepage and Jiannis Ragoussis and Guillaume Bourque and Jahad Alghamdi and Nora Aljawini and Nour Albes and Hani M Al-Afghani and Bader Alghamdi and Mansour S Almutairi and Ebrahim Sabri Mahmoud and Leen Abu-Safieh and Hadeel El Bardisy and Fawz S Al Harthi and Abdulraheem Alshareef and Bandar Ali Suliman and Saleh A Alqahtani and Abdulaziz Almalik and May M Alrashed and Salam Massadeh and Vincent Mooser and Mark Lathrop and Mohamed Fawzy and Yaseen M Arabi and Hamdi Mbarek and Chadi Saad and Wadha Al-Muftah and Junghyun Jung and Serghei Mangul and Radja Badji and Asma Al Thani and Said I Ismail and Ali G Gharavi and Malak S Abedalthagafi and J Brent Richards and David B Goldstein and Krzysztof Kiryluk},

doi = {10.1172/JCI147834},

issn = {1558-8238},

year  = {2021},

date = {2021-07-01},

journal = {J Clin Invest},

volume = {131},

number = {14},

abstract = {A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34215813b,

title = {Distinct roles of androgen receptor, estrogen receptor alpha, and BCL6 in the establishment of sex-biased DNA methylation in mouse liver},

author = {Najla AlOgayil and Klara Bauermeister and Jose Hector Galvez and Varun S Venkatesh and Qinwei Kim-Wee Zhuang and Matthew L Chang and Rachel A Davey and Jeffrey D Zajac and Kinuyo Ida and Akihide Kamiya and Teruko Taketo and Guillaume Bourque and Anna K Naumova},

doi = {10.1038/s41598-021-93216-6},

issn = {2045-2322},

year  = {2021},

date = {2021-07-01},

journal = {Sci Rep},

volume = {11},

number = {1},

pages = {13766},

abstract = {Sexual dimorphism in gene regulation, including DNA methylation, is the main driver of sexual dimorphism in phenotypes. However, the questions of how and when sex shapes DNA methylation remain unresolved. Recently, using mice with different combinations of genetic and phenotypic sex, we identified sex-associated differentially methylated regions (sDMRs) that depended on the sex phenotype. Focusing on a panel of validated sex-phenotype dependent male- and female-biased sDMRs, we tested the developmental dynamics of sex bias in liver methylation and the impacts of mutations in the androgen receptor, estrogen receptor alpha, or the transcriptional repressor Bcl6 gene. True hermaphrodites that carry both unilateral ovaries and contralateral testes were also tested. Our data show that sex bias in methylation either coincides with or follows sex bias in the expression of sDMR-proximal genes, suggesting that sex bias in gene expression may be required for demethylation at certain sDMRs. Global ablation of AR, ESR1, or a liver-specific loss of BCL6, all alter sDMR methylation, whereas presence of both an ovary and a testis delays the establishment of male-type methylation levels in hermaphrodites. Moreover, the Bcl6-LKO shows dissociation between expression and methylation, suggesting a distinct role of BCL6 in demethylation of intragenic sDMRs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34289352b,

title = {Whole-genome sequencing of H3K4me3 and DNA methylation in human sperm reveals regions of overlap linked to fertility and development},

author = {Romain Lambrot and Donovan Chan and Xiaojian Shao and Mahmoud Aarabi and Tony Kwan and Guillaume Bourque and Sergey Moskovtsev and Clifford Librach and Jacquetta Trasler and Vanessa Dumeaux and Sarah Kimmins},

doi = {10.1016/j.celrep.2021.109418},

issn = {2211-1247},

year  = {2021},

date = {2021-07-01},

journal = {Cell Rep},

volume = {36},

number = {3},

pages = {109418},

abstract = {The paternal environment has been linked to infertility and negative outcomes. Such effects may be transmitted via sperm through histone modifications. To date, in-depth profiling of the sperm chromatin in men has been limited. Here, we use deep sequencing to characterize the sperm profiles of histone H3 lysine 4 tri-methylation (H3K4me3) and DNA methylation in a representative reference population of 37 men. Our analysis reveals that H3K4me3 is localized throughout the genome and at genes for fertility and development. Remarkably, enrichment is also found at regions that escape epigenetic reprogramming in primordial germ cells, embryonic enhancers, and short-interspersed nuclear elements (SINEs). There is significant overlap in H3K4me3 and DNA methylation throughout the genome, suggesting a potential interplay between these marks previously reported to be mutually exclusive in sperm. Comparisons made between H3K4me3 marked regions in sperm and the embryonic transcriptome suggest an influence of paternal chromatin on embryonic gene expression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33976190b,

title = {A coordinated progression of progenitor cell states initiates urinary tract development},

author = {Oraly Sanchez-Ferras and Alain Pacis and Maria Sotiropoulou and Yuhong Zhang and Yu Chang Wang and Mathieu Bourgey and Guillaume Bourque and Jiannis Ragoussis and Maxime Bouchard},

doi = {10.1038/s41467-021-22931-5},

issn = {2041-1723},

year  = {2021},

date = {2021-05-01},

journal = {Nat Commun},

volume = {12},

number = {1},

pages = {2627},

abstract = {The kidney and upper urinary tract develop through reciprocal interactions between the ureteric bud and the surrounding mesenchyme. Ureteric bud branching forms the arborized collecting duct system of the kidney, while ureteric tips promote nephron formation from dedicated progenitor cells. While nephron progenitor cells are relatively well characterized, the origin of ureteric bud progenitors has received little attention so far. It is well established that the ureteric bud is induced from the nephric duct, an epithelial duct derived from the intermediate mesoderm of the embryo. However, the cell state transitions underlying the progression from intermediate mesoderm to nephric duct and ureteric bud remain unknown. Here we show that nephric duct morphogenesis results from the coordinated organization of four major progenitor cell populations. Using single cell RNA-seq and Cluster RNA-seq, we show that these progenitors emerge in time and space according to a stereotypical pattern. We identify the transcription factors Tfap2a/b and Gata3 as critical coordinators of this progenitor cell progression. This study provides a better understanding of the cellular origin of the renal collecting duct system and associated urinary tract developmental diseases, which may inform guided differentiation of functional kidney tissue.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33521749b,

title = {Cell-free DNA tissues of origin by methylation profiling reveals significant cell, tissue, and organ-specific injury related to COVID-19 severity},

author = {Alexandre Pellan Cheng and Matthew Pellan Cheng and Wei Gu and Joan Sesing Lenz and Elaine Hsu and Erwin Schurr and Guillaume Bourque and Mathieu Bourgey and Jerome Ritz and Francisco M Marty and Charles Y Chiu and Donald C Vinh and Iwijn De Vlaminck},

doi = {10.1016/j.medj.2021.01.001},

issn = {2666-6340},

year  = {2021},

date = {2021-04-01},

journal = {Med},

volume = {2},

number = {4},

pages = {411--422.e5},

abstract = {BACKGROUND: Coronavirus disease 2019 (COVID-19) primarily affects the lungs, but evidence of systemic disease with multi-organ involvement is emerging. Here, we developed a blood test to broadly quantify cell-, tissue-, and organ-specific injury due to COVID-19.



METHODS: Our test leverages genome-wide methylation profiling of circulating cell-free DNA in plasma. We assessed the utility of this test to identify subjects with severe disease in two independent, longitudinal cohorts of hospitalized patients. Cell-free DNA profiling was performed on 104 plasma samples from 33 COVID-19 patients and compared to samples from patients with other viral infections and healthy controls.



FINDINGS: We found evidence of injury to the lung and liver and involvement of red blood cell progenitors associated with severe COVID-19. The concentration of cell-free DNA correlated with the World Health Organization (WHO) ordinal scale for disease progression and was significantly increased in patients requiring intubation.



CONCLUSIONS: This study points to the utility of cell-free DNA as an analyte to monitor and study COVID-19.



FUNDING: This work was supported by NIH grants 1DP2AI138242 (to I.D.V.), R01AI146165 (to I.D.V., M.P.C., F.M.M., and J.R.), 1R01AI151059 (to I.D.V.), K08-CA230156 (to W.G.), and R33-AI129455 to C.Y.C., a Synergy award from the Rainin Foundation (to I.D.V.), a SARS-CoV-2 seed grant at Cornell (to I.D.V.), a National Sciences and Engineering Research Council of Canada fellowship PGS-D3 (to A.P.C.), and a Burroughs-Wellcome CAMS Award (to W.G.). D.C.V. is supported by a Fonds de la Recherche en Sante du Quebec Clinical Research Scholar Junior 2 award. C.Y.C. is supported by the California Initiative to Advance Precision Medicine, and the Charles and Helen Schwab Foundation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33731361b,

title = {Ultrafast functional profiling of RNA-seq data for nonmodel organisms},

author = {Peng Liu and Jessica Ewald and Jose Hector Galvez and Jessica Head and Doug Crump and Guillaume Bourque and Niladri Basu and Jianguo Xia},

doi = {10.1101/gr.269894.120},

issn = {1549-5469},

year  = {2021},

date = {2021-04-01},

journal = {Genome Res},

volume = {31},

number = {4},

pages = {713--720},

abstract = {Computational time and cost remain a major bottleneck for RNA-seq data analysis of nonmodel organisms without reference genomes. To address this challenge, we have developed Seq2Fun, a novel, all-in-one, ultrafast tool to directly perform functional quantification of RNA-seq reads without transcriptome de novo assembly. The pipeline starts with raw read quality control: sequencing error correction, removing poly(A) tails, and joining overlapped paired-end reads. It then conducts a DNA-to-protein search by translating each read into all possible amino acid fragments and subsequently identifies possible homologous sequences in a well-curated protein database. Finally, the pipeline generates several informative outputs including gene abundance tables, pathway and species hit tables, an HTML report to visualize the results, and an output of clean reads annotated with mapped genes ready for downstream analysis. Seq2Fun does not have any intermediate steps of file writing and loading, making I/O very efficient. Seq2Fun is written in C++ and can run on a personal computer with a limited number of CPUs and memory. It can process >2,000,000 reads/min and is >120 times faster than conventional workflows based on de novo assembly, while maintaining high accuracy in our various test data sets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34194450b,

title = {The Cowpea Kinome: Genomic and Transcriptomic Analysis Under Biotic and Abiotic Stresses},

author = {José Ribamar Costa Ferreira-Neto and Artemisa Nazaré da Costa Borges and Manassés Daniel da Silva and David Anderson de Lima Morais and João Pacífico Bezerra-Neto and Guillaume Bourque and Ederson Akio Kido and Ana Maria Benko-Iseppon},

doi = {10.3389/fpls.2021.667013},

issn = {1664-462X},

year  = {2021},

date = {2021-01-01},

journal = {Front Plant Sci},

volume = {12},

pages = {667013},

abstract = {The present work represents a pioneering effort, being the first to analyze genomic and transcriptomic data from  (cowpea) kinases. We evaluated the cowpea kinome considering its genome-wide distribution and structural characteristics (at the gene and protein levels), sequence evolution, conservation among Viridiplantae species, and gene expression in three cowpea genotypes under different stress situations, including biotic (injury followed by virus inoculation-CABMV or CPSMV) and abiotic (root dehydration). The structural features of cowpea kinases (VuPKs) indicated that 1,293  VuPKs covered 20 groups and 118 different families. The RLK-Pelle was the largest group, with 908 members. Insights on the mechanisms of VuPK genomic expansion and conservation among Viridiplantae species indicated dispersed and tandem duplications as major forces for VuPKs' distribution pattern and high orthology indexes and synteny with other legume species, respectively.   /  ratios showed that almost all (91%) of the tandem duplication events were under purifying selection. Candidate -regulatory elements were associated with different transcription factors (TFs) in the promoter regions of the RLK-Pelle group. C2H2 TFs were closely associated with the promoter regions of almost all scrutinized families for the mentioned group. At the transcriptional level, it was suggested that VuPK up-regulation was stress, genotype, or tissue dependent (or a combination of them). The most prominent families in responding (up-regulation) to all the analyzed stresses were RLK-Pelle_DLSV and CAMK_CAMKL-CHK1. Concerning root dehydration, it was suggested that the up-regulated VuPKs are associated with ABA hormone signaling, auxin hormone transport, and potassium ion metabolism. Additionally, up-regulated VuPKs under root dehydration potentially assist in a critical physiological strategy of the studied cowpea genotype in this assay, with activation of defense mechanisms against biotic stress while responding to root dehydration. This study provides the foundation for further studies on the evolution and molecular function of VuPKs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34335193b,

title = {Single Cell Transcriptomics of Ependymal Cells Across Age, Region and Species Reveals Cilia-Related and Metal Ion Regulatory Roles as Major Conserved Ependymal Cell Functions},

author = {Adam MacDonald and Brianna Lu and Maxime Caron and Nina Caporicci-Dinucci and Dale Hatrock and Kevin Petrecca and Guillaume Bourque and Jo Anne Stratton},

doi = {10.3389/fncel.2021.703951},

issn = {1662-5102},

year  = {2021},

date = {2021-01-01},

journal = {Front Cell Neurosci},

volume = {15},

pages = {703951},

abstract = {Ependymal cells are ciliated-epithelial glial cells that develop from radial glia along the surface of the ventricles of the brain and the spinal canal. They play a critical role in cerebrospinal fluid (CSF) homeostasis, brain metabolism, and the clearance of waste from the brain. These cells have been implicated in disease across the lifespan including developmental disorders, cancer, and neurodegenerative disease. Despite this, ependymal cells remain largely understudied. Using single-cell RNA sequencing data extracted from publicly available datasets, we make key findings regarding the remarkable conservation of ependymal cell gene signatures across age, region, and species. Through this unbiased analysis, we have discovered that one of the most overrepresented ependymal cell functions that we observed relates to a  understudied role in metal ion homeostasis. Our analysis also revealed distinct subtypes and states of ependymal cells across regions and ages of the nervous system. For example, neonatal ependymal cells maintained a gene signature consistent with developmental processes such as determination of left/right symmetry; while adult ventricular ependymal cells, not spinal canal ependymal cells, appeared to express genes involved in regulating cellular transport and inflammation. Together, these findings highlight underappreciated functions of ependymal cells, which will be important to investigate in order to better understand these cells in health and disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34590283b,

title = {Inferring Copy Number from Triple-Negative Breast Cancer Patient Derived Xenograft scRNAseq Data Using scCNA},

author = {Elena Kuzmin and Jean Monlong and Constanza Martinez and Hellen Kuasne and Claudia L Kleinman and Jiannis Ragoussis and Guillaume Bourque and Morag Park},

doi = {10.1007/978-1-0716-1740-3_16},

issn = {1940-6029},

year  = {2021},

date = {2021-01-01},

journal = {Methods Mol Biol},

volume = {2381},

pages = {285--303},

abstract = {Cancer can develop from an accumulation of alterations, some of which cause a nonmalignant cell to transform to a malignant state exhibiting increased rate of cell growth and evasion of growth suppressive mechanisms, eventually leading to tissue invasion and metastatic disease. Triple-negative breast cancers (TNBC) are heterogeneous and are clinically characterized by the lack of expression of hormone receptors and human epidermal growth factor receptor 2 (HER2), which limits its treatment options. Since tumor evolution is driven by diverse cancer cell populations and their microenvironment, it is imperative to map TNBC at single-cell resolution. Here, we describe an experimental procedure for isolating a single-cell suspension from a TNBC patient-derived xenograft, subjecting it to single-cell RNA sequencing using droplet-based technology from 10× Genomics and analyzing the transcriptomic data at single-cell resolution to obtain inferred copy number aberration profiles, using scCNA. Data obtained using this single-cell RNA sequencing experimental and analytical methodology should enhance our understanding of intratumor heterogeneity which is key for identifying genetic vulnerabilities and developing effective therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{brereton_reanalysis_2021,

title = {Reanalysis of the Mars500 experiment reveals common gut microbiome alterations in astronauts induced by long-duration confinement},

author = {N J B Brereton and F E Pitre and E Gonzalez},

url = {https://www.sciencedirect.com/science/article/pii/S2001037021001306},

doi = {10.1016/j.csbj.2021.03.040},

issn = {2001-0370},

year  = {2021},

date = {2021-01-01},

urldate = {2021-05-28},

journal = {Computational and Structural Biotechnology Journal},

volume = {19},

pages = {2223--2235},

abstract = {Maintaining astronaut health throughout long-duration spaceflight is essential to the feasibility of a manned mission to Mars. The ground-based Mars500 experiment investigated long-duration health by isolating six astronauts for 520 days, the longest controlled human confinement study conducted to date. After 520 days, astronauts had uniform strength and lean body mass losses, and increased fasting plasma glucose, calprotectin, and neutrophil levels characteristic of intestinal inflammation but previous analyses revealed no common significant changes in gut microbiota. This study reanalysed data from early (days 7–45) and late (days 420–520) faecal samples and identified 408 exact sequence variants (ESVs), including 213 shared by all astronauts. Thirty-two ESVs were significantly differentially abundant over time, including depletion of keystone resistant starch degrading, anti-inflammatory and insulin sensitivity-associated species, such as Faecalibacterium prausnitzii, Ruminococcus bromii, Blautia luti, Anaerostipes hadrus, Roseburia faecis, and Lactobacillus rogosae, and enrichment of yet-to-be-cultured bacteria. Additionally, the extraordinary experimental confinement allowed observation of microbiota potentially shared between astronauts and their habitat. Forty-nine species were shared, representing 49% and 12% of the human and environmental microbiome diversity, respectively. These findings reveal the microbiota which significantly altered in relative abundance throughout confinement, including species known to influence inflammation and host glucose homeostasis consistent with astronaut symptoms. Identification of microbiome alterations after 520 days of isolation represents a missing piece connecting Mars500 astronaut physiological studies. Knowledge of the impact of long-term confinement upon the human microbiome helps to improve our understanding of how humans interact with their habitats and is a valuable step forward towards enabling long-duration spaceflight.},

keywords = {16S rRNA gene, Astronaut health, Mars, Microbiome, Space science},

pubstate = {published},

tppubtype = {article}

}

@article{el-far_upregulated_2021,

title = {Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis},

author = {Mohamed El-Far and Madeleine Durand and Isabelle Turcotte and Etienne Larouche-Anctil and Mohamed Sylla and Sarah Zaidan and Carl Chartrand-Lefebvre and Rémi Bunet and Hardik Ramani and Manel Sadouni and Irina Boldeanu and Annie Chamberland and Sylvie Lesage and Jean-Guy Baril and Benoit Trottier and Réjean Thomas and Emmanuel Gonzalez and Ali Filali-Mouhim and Jean-Philippe Goulet and Jeffrey A Martinson and Seble Kassaye and Roksana Karim and Jorge R Kizer and Audrey L French and Stephen J Gange and Petronela Ancuta and Jean-Pierre Routy and David B Hanna and Robert C Kaplan and Nicolas Chomont and Alan L Landay and Cécile L Tremblay},

url = {https://www.frontiersin.org/articles/10.3389/fimmu.2021.664371/full},

doi = {10.3389/fimmu.2021.664371},

issn = {1664-3224},

year  = {2021},

date = {2021-01-01},

urldate = {2021-05-28},

journal = {Frontiers in Immunology},

volume = {12},

abstract = {Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, β, γ, D, ε, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1β and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our in vitro functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; Rothia and Eggerthella species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1β in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH.},

note = {Publisher: Frontiers},

keywords = {Atherosclerosis, CVD (cardio vascular disease), gut microbiome, HIV, IL-32, Inflammation, short-chain fatty acids},

pubstate = {published},

tppubtype = {article}

}

@article{lopezleyva_human_2021b,

title = {Human Milk Microbiota in an Indigenous Population Is Associated with Maternal Factors, Stage of Lactation, and Breastfeeding Practices},

author = {Lilian Lopez Leyva and Emmanuel Gonzalez and Chen Li and Tamara Ajeeb and Noel W Solomons and Luis B Agellon and Marilyn E Scott and Kristine G Koski},

url = {https://doi.org/10.1093/cdn/nzab013},

doi = {10.1093/cdn/nzab013},

issn = {2475-2991},

year  = {2021},

date = {2021-01-01},

urldate = {2021-05-28},

journal = {Current Developments in Nutrition},

volume = {5},

number = {nzab013},

abstract = {Human milk contains a diverse community of bacteria that are modified by maternal factors, but whether these or other factors are similar in developing countries has not been explored. Our objective was to determine whether the milk microbiota was modified by maternal age, BMI, parity, lactation stage, subclinical mastitis (SCM), and breastfeeding practices in the first 6 mo of lactation in an indigenous population from Guatemala.For this cross-sectional study, Mam-Mayan indigenous mothers nursing infants aged <6 mo were recruited. Unilateral human milk samples were collected (n = 86) and processed for 16S rRNA sequencing at the genus level. Microbial diversity and relative abundance were compared with maternal factors [age, BMI, parity, stage of lactation, SCM, and 3 breastfeeding practices (exclusive, predominant, mixed)] obtained through questionnaires.Streptococcus was the most abundant genus (33.8%), followed by Pseudomonas (18.7%) and Sphingobium (10.7%) but relative abundance was associated with maternal factors. First, Lactobacillus and Streptococcus were more abundant in early lactation whereas the common oral (Leptotrichia) and environmental (Comamonas) bacteria were more abundant in established lactation. Second, Streptococcus,Lactobacillus,Lactococcus,Leuconostoc, and Micrococcus had a higher abundance in multiparous mothers compared with primiparous mothers. Third, a more diverse microbiota characterized by a higher abundance of lactic acid bacteria (Lactobacillus,Leuconostoc, and Lactococcus), Leucobacter, and Micrococcus was found in mothers with a healthy BMI. Finally, distinct microbial communities differed by stage of lactation and by exclusive, predominant, or mixed breastfeeding practices.Milk bacterial communities in an indigenous community were associated with maternal factors. Higher microbial diversity was supported by having a healthy BMI, the absence of SCM, and by breastfeeding. Interestingly, breastfeeding practices when assessed by lactation stage were associated with distinct microbiota profiles.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}