Publications

@article{pmid27863232,

title = {The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery},

author = {Hendrik G Stunnenberg and  and Martin Hirst},

doi = {10.1016/j.cell.2016.11.007},

issn = {1097-4172},

year  = {2016},

date = {2016-11-01},

journal = {Cell},

volume = {167},

number = {5},

pages = {1145--1149},

abstract = {The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalog of high-resolution reference epigenomes of major primary human cell types. The studies now presented (see the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic datasets to gain insights in the epigenetic control of cell states relevant for human health and disease. PAPERCLIP.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27851974,

title = {eFORGE: A Tool for Identifying Cell Type-Specific Signal in Epigenomic Data},

author = {Charles E Breeze and Dirk S Paul and Jenny van Dongen and Lee M Butcher and John C Ambrose and James E Barrett and Robert Lowe and Vardhman K Rakyan and Valentina Iotchkova and Mattia Frontini and Kate Downes and Willem H Ouwehand and Jonathan Laperle and Pierre-Étienne Jacques and Guillaume Bourque and Anke K Bergmann and Reiner Siebert and Edo Vellenga and Sadia Saeed and Filomena Matarese and Joost H A Martens and Hendrik G Stunnenberg and Andrew E Teschendorff and Javier Herrero and Ewan Birney and Ian Dunham and Stephan Beck},

doi = {10.1016/j.celrep.2016.10.059},

issn = {2211-1247},

year  = {2016},

date = {2016-11-01},

journal = {Cell Rep},

volume = {17},

number = {8},

pages = {2137--2150},

abstract = {Epigenome-wide association studies (EWAS) provide an alternative approach for studying human disease through consideration of non-genetic variants such as altered DNA methylation. To advance the complex interpretation of EWAS, we developed eFORGE (http://eforge.cs.ucl.ac.uk/), a new standalone and web-based tool for the analysis and interpretation of EWAS data. eFORGE determines the cell type-specific regulatory component of a set of EWAS-identified differentially methylated positions. This is achieved by detecting enrichment of overlap with DNase I hypersensitive sites across 454 samples (tissues, primary cell types, and cell lines) from the ENCODE, Roadmap Epigenomics, and BLUEPRINT projects. Application of eFORGE to 20 publicly available EWAS datasets identified disease-relevant cell types for several common diseases, a stem cell-like signature in cancer, and demonstrated the ability to detect cell-composition effects for EWAS performed on heterogeneous tissues. Our approach bridges the gap between large-scale epigenomics data and EWAS-derived target selection to yield insight into disease etiology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27791185,

title = {Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2},

author = {Soroush Tahmasebi and Seyed Mehdi Jafarnejad and Ingrid S Tam and Thomas Gonatopoulos-Pournatzis and Edna Matta-Camacho and Yoshinori Tsukumo and Akiko Yanagiya and Wencheng Li and Yaser Atlasi and Maxime Caron and Ulrich Braunschweig and Dana Pearl and Arkady Khoutorsky and Christos G Gkogkas and Robert Nadon and Guillaume Bourque and Xiang-Jiao Yang and Bin Tian and Hendrik G Stunnenberg and Yojiro Yamanaka and Benjamin J Blencowe and Vincent Giguère and Nahum Sonenberg},

doi = {10.1073/pnas.1615540113},

issn = {1091-6490},

year  = {2016},

date = {2016-11-01},

journal = {Proc Natl Acad Sci U S A},

volume = {113},

number = {44},

pages = {12360--12367},

abstract = {Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-β (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tract-binding protein 1 (PTBP1) promotes the retention of an intron in the 5'-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27624058,

title = {Immunoseq: the identification of functionally relevant variants through targeted capture and sequencing of active regulatory regions in human immune cells},

author = {Andréanne Morin and Tony Kwan and Bing Ge and Louis Letourneau and Maria Ban and Karolina Tandre and Maxime Caron and Johanna K Sandling and Jonas Carlsson and Guillaume Bourque and Catherine Laprise and Alexandre Montpetit and Ann-Christine Syvanen and Lars Ronnblom and Stephen J Sawcer and Mark G Lathrop and Tomi Pastinen},

doi = {10.1186/s12920-016-0220-7},

issn = {1755-8794},

year  = {2016},

date = {2016-09-01},

journal = {BMC Med Genomics},

volume = {9},

number = {1},

pages = {59},

abstract = {BACKGROUND: The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells - "Immunoseq".



RESULTS: We performed Immunoseq in 30 healthy individuals where we had existing transcriptome data from T cells. We identified a large number of novel non-coding variants in these samples. Relying on allele specific expression measurements, we also showed that our selected capture regions are enriched for functional variants that have an impact on differential allelic gene expression. The results from a replication set with 180 samples confirmed our observations.



CONCLUSIONS: We show that Immunoseq is a powerful approach to detect novel rare variants in regulatory regions. We also demonstrate that these novel variants have a potential functional role in immune cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27990475b,

title = {Evolving data access policy: The Canadian context},

author = {Stephanie O M Dyke and Katie M Saulnier and Tomi Pastinen and Guillaume Bourque and Yann Joly},

doi = {10.1139/facets-2016-0002},

issn = {2371-1671},

year  = {2016},

date = {2016-09-01},

journal = {Facets (Ott)},

volume = {1},

number = {1},

pages = {138--147},

abstract = {In setting up a data access policy to share controlled access data from the McGill Epigenomics Mapping Centre (EMC), an International Human Epigenome Consortium (IHEC) partner project, we encountered ethical and legal challenges that are likely to be relevant to other researchers sharing data, especially from Canadian projects. We discuss our solutions to the following data-sharing challenges, based on comparative legal and policy analysis: (1) providing access to data to a growing number of researchers; (2) maintaining Canadian privacy standards while sharing controlled access data internationally; (3) freedom of information requests; and (4) providing more incentives for researchers to share pre-publication data.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27402251,

title = {ERRα mediates metabolic adaptations driving lapatinib resistance in breast cancer},

author = {Geneviève Deblois and Harvey W Smith and Ingrid S Tam and Simon-Pierre Gravel and Maxime Caron and Paul Savage and David P Labbé and Louis R Bégin and Michel L Tremblay and Morag Park and Guillaume Bourque and Julie St-Pierre and William J Muller and Vincent Giguère},

doi = {10.1038/ncomms12156},

issn = {2041-1723},

year  = {2016},

date = {2016-07-01},

journal = {Nat Commun},

volume = {7},

pages = {12156},

abstract = {Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERRα-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27037229,

title = {ABCA7 rare variants and Alzheimer disease risk},

author = {Kilan Le Guennec and Gaël Nicolas and Olivier Quenez and Camille Charbonnier and David Wallon and Céline Bellenguez and Benjamin Grenier-Boley and Stéphane Rousseau and Anne-Claire Richard and Anne Rovelet-Lecrux and Delphine Bacq and Jean-Guillaume Garnier and Robert Olaso and Anne Boland and Vincent Meyer and Jean-François Deleuze and Philippe Amouyel and Hans Markus Munter and Guillaume Bourque and Mark Lathrop and Thierry Frebourg and Richard Redon and Luc Letenneur and Jean-François Dartigues and Florence Pasquier and Adeline Rollin-Sillaire and Emmanuelle Génin and Jean-Charles Lambert and Didier Hannequin and Dominique Campion and },

doi = {10.1212/WNL.0000000000002627},

issn = {1526-632X},

year  = {2016},

date = {2016-06-01},

journal = {Neurology},

volume = {86},

number = {23},

pages = {2134--2137},

abstract = {OBJECTIVE: To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting.



METHODS: We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls.



RESULTS: After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.68-7.35, p = 0.0002). Performing a meta-analysis with previously published data, we found that in a combined sample of 1,256 patients and 1,347 controls from France and Belgium, the OR was 2.81 (95% CI 1.89-4.20, p = 3.60 × 10(-7)).



CONCLUSIONS: These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26242991,

title = {Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons},

author = {Gaël Nicolas and David Wallon and Camille Charbonnier and Olivier Quenez and Stéphane Rousseau and Anne-Claire Richard and Anne Rovelet-Lecrux and Sophie Coutant and Kilan Le Guennec and Delphine Bacq and Jean-Guillaume Garnier and Robert Olaso and Anne Boland and Vincent Meyer and Jean-François Deleuze and Hans Markus Munter and Guillaume Bourque and Daniel Auld and Alexandre Montpetit and Mark Lathrop and Lucie Guyant-Maréchal and Olivier Martinaud and Jérémie Pariente and Adeline Rollin-Sillaire and Florence Pasquier and Isabelle Le Ber and Marie Sarazin and Bernard Croisile and Claire Boutoleau-Bretonnière and Catherine Thomas-Antérion and Claire Paquet and Mathilde Sauvée and Olivier Moreaud and Audrey Gabelle and François Sellal and Mathieu Ceccaldi and Ludivine Chamard and Frédéric Blanc and Thierry Frebourg and Dominique Campion and Didier Hannequin},

doi = {10.1038/ejhg.2015.173},

issn = {1476-5438},

year  = {2016},

date = {2016-05-01},

journal = {Eur J Hum Genet},

volume = {24},

number = {5},

pages = {710--716},

abstract = {Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32328532b,

title = {Variations in 5-methylcytosine and 5-hydroxymethylcytosine among human brain, blood, and saliva using oxBS and the Infinium MethylationEPIC array},

author = {Jeffrey A Gross and François Lefebvre and Pierre-Eric Lutz and François Bacot and Daniel Vincent and Guillaume Bourque and Gustavo Turecki},

doi = {10.1093/biomethods/bpw002},

issn = {2396-8923},

year  = {2016},

date = {2016-03-01},

journal = {Biol Methods Protoc},

volume = {1},

number = {1},

pages = {1--8},

abstract = {Investigating 5-methylcytosine (5mC) has led to many hypotheses regarding molecular mechanism underlying human diseases and disorders. Many of these studies, however, utilize bisulfite conversion alone, which cannot distinguish 5mC from its recently discovered oxidative product, 5-hydroxymethylcytosine (5hmC). Furthermore, previous array-based technologies do not have the necessary probes to adequately investigate both modifications simultaneously. In this manuscript, we used technical replicates of DNA from human brain, human blood, and human saliva, in combination with oxidative bisulfite conversion and Illumina's Infinium MethylationEPIC array, to analyze 5mC and 5hmC at more than 650 000 and 450 000 relevant loci, respectively, in the human genome. We show the presence of loci with detectable 5mC and 5hmC to be equally distributed across chromosomes and genomic features, while also being present in genomic regions with transcriptional regulatory properties. We also describe 2528 5hmC sites common across tissue types that show a strong association with immune-related functions. Lastly, in human brain, we show that 5hmC accounts for one-third of the total signal from bisulfite-converted data. As such, not only do our results confirm the efficacy and sensitivity of pairing oxidative bisulfite conversion and the EPIC array to detect 5mC and 5hmC in all three tissue types, but they also highlight the importance of dissociating 5hmC from 5mC in future studies related to cytosine modifications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26804918,

title = {The PGC-1α/ERRα Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-folate Therapy in Breast Cancer},

author = {Étienne Audet-Walsh and David J Papadopoli and Simon-Pierre Gravel and Tracey Yee and Gaëlle Bridon and Maxime Caron and Guillaume Bourque and Vincent Giguère and Julie St-Pierre},

doi = {10.1016/j.celrep.2015.12.086},

issn = {2211-1247},

year  = {2016},

date = {2016-02-01},

journal = {Cell Rep},

volume = {14},

number = {4},

pages = {920--931},

abstract = {Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1α/ERRα axis are key regulators of this process. The intersection of gene-expression and binding-event datasets for breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27581031,

title = {RNA-Seq as a Tool to Study the Tumor Microenvironment},

author = {Pudchalaluck Panichnantakul and Mathieu Bourgey and Alexandre Montpetit and Guillaume Bourque and Yasser Riazalhosseini},

doi = {10.1007/978-1-4939-3801-8_22},

issn = {1940-6029},

year  = {2016},

date = {2016-01-01},

journal = {Methods Mol Biol},

volume = {1458},

pages = {311--337},

abstract = {The transcriptome is composed of different types of RNA molecules including mRNAs, tRNAs, rRNAs, and other noncoding RNAs that are found inside a cell at a given time. Analyzing transcriptome patterns can shed light on the functional state of the cell as well as on the dynamics of cellular behavior associated with genomic and environmental changes. Likewise, transcriptome analysis has been a major help in solving biological issues and understanding the molecular basis of many diseases including human cancers. Specifically, since targeted and whole genome sequencing studies are becoming more common in identifying the driving factors of cancer, a comprehensive and high-resolution analysis of the transcriptome, as provided by RNA-Sequencing (RNA-Seq), plays a key role in investigating the functional relevance of the identified genomic aberrations. Here, we describe experimental procedures of RNA-Seq and downstream data processing and analysis, with a focus on the identification of abnormally expressed transcripts and genes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26895045,

title = {In Silico Methods to Identify Exapted Transposable Element Families},

author = {LeeAnn Ramsay and Guillaume Bourque},

doi = {10.1007/978-1-4939-3372-3_3},

issn = {1940-6029},

year  = {2016},

date = {2016-01-01},

journal = {Methods Mol Biol},

volume = {1400},

pages = {33--45},

abstract = {Transposable elements (TEs) have recently been shown to have many regulatory roles within the genome. In this chapter, we will examine two in silico methods for analyzing TEs and identifying families that may have acquired such functions. The first method will look at how the overrepresentation of a repeat family in a set of genomic features can be discovered. The example situation of OCT4 binding sites originating from LTR7 TE sequences will be used to show how this method could be applied. The second method will describe how to determine if a TE family exhibits a cell type-specific expression pattern. As an example, we will look at the expression of HERV-H, an endogenous retrovirus known to act as an lncRNA in embryonic stem cells. We will use this example to demonstrate how RNA-seq data can be used to compare cell type expression of repeats.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26699896,

title = {Population whole-genome bisulfite sequencing across two tissues highlights the environment as the principal source of human methylome variation},

author = {Stephan Busche and Xiaojian Shao and Maxime Caron and Tony Kwan and Fiona Allum and Warren A Cheung and Bing Ge and Susan Westfall and Marie-Michelle Simon and  and Amy Barrett and Jordana T Bell and Mark I McCarthy and Panos Deloukas and Mathieu Blanchette and Guillaume Bourque and Timothy D Spector and Mark Lathrop and Tomi Pastinen and Elin Grundberg},

doi = {10.1186/s13059-015-0856-1},

issn = {1474-760X},

year  = {2015},

date = {2015-12-01},

journal = {Genome Biol},

volume = {16},

pages = {290},

abstract = {BACKGROUND: CpG methylation variation is involved in human trait formation and disease susceptibility. Analyses within populations have been biased towards CpG-dense regions through the application of targeted arrays. We generate whole-genome bisulfite sequencing data for approximately 30 adipose and blood samples from monozygotic and dizygotic twins for the characterization of non-genetic and genetic effects at single-site resolution.



RESULTS: Purely invariable CpGs display a bimodal distribution with enrichment of unmethylated CpGs and depletion of fully methylated CpGs in promoter and enhancer regions. Population-variable CpGs account for approximately 15-20 % of total CpGs per tissue, are enriched in enhancer-associated regions and depleted in promoters, and single nucleotide polymorphisms at CpGs are a frequent confounder of extreme methylation variation. Differential methylation is primarily non-genetic in origin, with non-shared environment accounting for most of the variance. These non-genetic effects are mainly tissue-specific. Tobacco smoking is associated with differential methylation in blood with no evidence of this exposure impacting cell counts. Opposite to non-genetic effects, genetic effects of CpG methylation are shared across tissues and thus limit inter-tissue epigenetic drift. CpH methylation is rare, and shows similar characteristics of variation patterns as CpGs.



CONCLUSIONS: Our study highlights the utility of low pass whole-genome bisulfite sequencing in identifying methylome variation beyond promoter regions, and suggests that targeting the population dynamic methylome of tissues requires assessment of understudied intergenic CpGs distal to gene promoters to reveal the full extent of inter-individual variation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26307085,

title = {High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism},

author = {Mahmoud Aarabi and Maria C San Gabriel and Donovan Chan and Nathalie A Behan and Maxime Caron and Tomi Pastinen and Guillaume Bourque and Amanda J MacFarlane and Armand Zini and Jacquetta Trasler},

doi = {10.1093/hmg/ddv338},

issn = {1460-2083},

year  = {2015},

date = {2015-11-01},

journal = {Hum Mol Genet},

volume = {24},

number = {22},

pages = {6301--6313},

abstract = {Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodeled during spermatogenesis. While high-dose folic acid supplementation (up to 10 times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of 6 months of high-dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG-density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high-dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26185018,

title = {Epigenome data release: a participant-centered approach to privacy protection},

author = {Stephanie O M Dyke and Warren A Cheung and Yann Joly and Ole Ammerpohl and Pavlo Lutsik and Mark A Rothstein and Maxime Caron and Stephan Busche and Guillaume Bourque and Lars Rönnblom and Paul Flicek and Stephan Beck and Martin Hirst and Henk Stunnenberg and Reiner Siebert and Jörn Walter and Tomi Pastinen},

doi = {10.1186/s13059-015-0723-0},

issn = {1474-760X},

year  = {2015},

date = {2015-07-01},

journal = {Genome Biol},

volume = {16},

number = {1},

pages = {142},

abstract = {Large-scale epigenome mapping by the NIH Roadmap Epigenomics Project, the ENCODE Consortium and the International Human Epigenome Consortium (IHEC) produces genome-wide DNA methylation data at one base-pair resolution. We examine how such data can be made open-access while balancing appropriate interpretation and genomic privacy. We propose guidelines for data release that both reduce ambiguity in the interpretation of open-access data and limit immediate access to genetic variation data that are made available through controlled access.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25646748,

title = {A replication study for association of 53 single nucleotide polymorphisms in ScoliScore test with adolescent idiopathic scoliosis in French-Canadian population},

author = {Qi Lin Tang and Cedric Julien and Robert Eveleigh and Guillaume Bourque and Anita Franco and Hubert Labelle and Guy Grimard and Stefan Parent and Jean Ouellet and Jean-Marc Mac-Thiong and Kristen F Gorman and Alain Moreau},

doi = {10.1097/BRS.0000000000000807},

issn = {1528-1159},

year  = {2015},

date = {2015-04-01},

journal = {Spine (Phila Pa 1976)},

volume = {40},

number = {8},

pages = {537--543},

abstract = {STUDY DESIGN: A replication association study that used genomic data generated from French-Canadian case and control cohorts.



OBJECTIVES: To determine whether the 53 single nucleotide polymorphisms (SNPs) that were previously associated with spinal deformity progression in an American Caucasian cohort are similarly associated in French-Canadian population.



SUMMARY OF BACKGROUND DATA: It is widely accepted that genetic factors contribute to adolescent idiopathic scoliosis. The identification of genetic variants associated with the predisposition or progression of curvature could facilitate diagnostic/prognostic tool development. Although 53 SNPs have been associated with spinal curve progression in Caucasian cohorts in the United States, these associations were not replicated in a large Japanese population study, arguing that such a discrepancy could be explained by ethnicity, thus raising the importance of a replication study in an independent Caucasian population of European descent.



METHODS: Genomic data were collected from the French-Canadian population, using the Illumina HumanOmni 2.5M BeadChip. Fifty-two SNPs, tested in ScoliScore or in high linkage disequilibrium with SNPs in the test, were selected to assess their association with scoliosis generally, and with spinal curve progression. One SNP in ScoliScore, rs16909285, could not be evaluated in our Genome-Wide association study.



RESULTS: None of the SNPs used in ScoliScore were associated with adolescent idiopathic scoliosis curve progression or curve occurrence in French-Canadian population. We evaluated 52 SNPs in severe patients by comparing risk allele frequencies with those in nonsevere patients and with those in control individuals. There was no significant difference between the severe group and the nonsevere group or between the severe group and the control group.



CONCLUSION: Although the 52 SNPs studied here were previously associated with curve progression in an American population of European descent, we found no association in French-Canadian patients with adolescent idiopathic scoliosis. This second replication cohort suggests that the lack of association of these SNPs in a Japanese cohort is not due to ethnicity.



LEVEL OF EVIDENCE: 4.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25578964,

title = {Transient DNMT1 suppression reveals hidden heritable marks in the genome},

author = {Serge McGraw and Jacques X Zhang and Mena Farag and Donovan Chan and Maxime Caron and Carolin Konermann and Christopher C Oakes and K Naga Mohan and Christoph Plass and Tomi Pastinen and Guillaume Bourque and J Richard Chaillet and Jacquetta M Trasler},

doi = {10.1093/nar/gku1386},

issn = {1362-4962},

year  = {2015},

date = {2015-02-01},

journal = {Nucleic Acids Res},

volume = {43},

number = {3},

pages = {1485--1497},

abstract = {Genome-wide demethylation and remethylation of DNA during early embryogenesis is essential for development. Imprinted germline differentially methylated domains (gDMDs) established by sex-specific methylation in either male or female germ cells, must escape these dynamic changes and sustain precise inheritance of both methylated and unmethylated parental alleles. To identify other, gDMD-like sequences with the same epigenetic inheritance properties, we used a modified embryonic stem (ES) cell line that emulates the early embryonic demethylation and remethylation waves. Transient DNMT1 suppression revealed gDMD-like sequences requiring continuous DNMT1 activity to sustain a highly methylated state. Remethylation of these sequences was also compromised in vivo in a mouse model of transient DNMT1 loss in the preimplantation embryo. These novel regions, possessing heritable epigenetic features similar to imprinted-gDMDs are required for normal physiological and developmental processes and when disrupted are associated with disorders such as cancer and autism spectrum disorders. This study presents new perspectives on DNA methylation heritability during early embryo development that extend beyond conventional imprinted-gDMDs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26244060,

title = {A call for benchmarking transposable element annotation methods},

author = {Douglas R Hoen and Glenn Hickey and Guillaume Bourque and Josep Casacuberta and Richard Cordaux and Cédric Feschotte and Anna-Sophie Fiston-Lavier and Aurélie Hua-Van and Robert Hubley and Aurélie Kapusta and Emmanuelle Lerat and Florian Maumus and David D Pollock and Hadi Quesneville and Arian Smit and Travis J Wheeler and Thomas E Bureau and Mathieu Blanchette},

doi = {10.1186/s13100-015-0044-6},

issn = {1759-8753},

year  = {2015},

date = {2015-01-01},

journal = {Mob DNA},

volume = {6},

pages = {13},

abstract = {DNA derived from transposable elements (TEs) constitutes large parts of the genomes of complex eukaryotes, with major impacts not only on genomic research but also on how organisms evolve and function. Although a variety of methods and tools have been developed to detect and annotate TEs, there are as yet no standard benchmarks-that is, no standard way to measure or compare their accuracy. This lack of accuracy assessment calls into question conclusions from a wide range of research that depends explicitly or implicitly on TE annotation. In the absence of standard benchmarks, toolmakers are impeded in improving their tools, annotators cannot properly assess which tools might best suit their needs, and downstream researchers cannot judge how accuracy limitations might impact their studies. We therefore propose that the TE research community create and adopt standard TE annotation benchmarks, and we call for other researchers to join the authors in making this long-overdue effort a success.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25307298,

title = {Molecular convergence of neurodevelopmental disorders},

author = {Elizabeth S Chen and Carolina O Gigek and Jill A Rosenfeld and Alpha B Diallo and Gilles Maussion and Gary G Chen and Kathryn Vaillancourt and Juan P Lopez and Liam Crapper and Raphaël Poujol and Lisa G Shaffer and Guillaume Bourque and Carl Ernst},

doi = {10.1016/j.ajhg.2014.09.013},

issn = {1537-6605},

year  = {2014},

date = {2014-11-01},

journal = {Am J Hum Genet},

volume = {95},

number = {5},

pages = {490--508},

abstract = {Neurodevelopmental disorders (NDDs) are caused by mutations in diverse genes involved in different cellular functions, although there can be crosstalk, or convergence, between molecular pathways affected by different NDDs. To assess molecular convergence, we generated human neural progenitor cell models of 9q34 deletion syndrome, caused by haploinsufficiency of EHMT1, and 18q21 deletion syndrome, caused by haploinsufficiency of TCF4. Using next-generation RNA sequencing, methylation sequencing, chromatin immunoprecipitation sequencing, and whole-genome miRNA analysis, we identified several levels of convergence. We found mRNA and miRNA expression patterns that were more characteristic of differentiating cells than of proliferating cells, and we identified CpG clusters that had similar methylation states in both models of reduced gene dosage. There was significant overlap of gene targets of TCF4 and EHMT1, whereby 8.3% of TCF4 gene targets and 4.2% of EHMT1 gene targets were identical. These data suggest that 18q21 and 9q34 deletion syndromes show significant molecular convergence but distinct expression and methylation profiles. Common intersection points might highlight the most salient features of disease and provide avenues for similar treatments for NDDs caused by different genetic mutations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25351205,

title = {Variation in genomic landscape of clear cell renal cell carcinoma across Europe},

author = {Ghislaine Scelo and Yasser Riazalhosseini and Liliana Greger and Louis Letourneau and Mar Gonzàlez-Porta and Magdalena B Wozniak and Mathieu Bourgey and Patricia Harnden and Lars Egevad and Sharon M Jackson and Mehran Karimzadeh and Madeleine Arseneault and Pierre Lepage and Alexandre How-Kit and Antoine Daunay and Victor Renault and Hélène Blanché and Emmanuel Tubacher and Jeremy Sehmoun and Juris Viksna and Edgars Celms and Martins Opmanis and Andris Zarins and Naveen S Vasudev and Morag Seywright and Behnoush Abedi-Ardekani and Christine Carreira and Peter J Selby and Jon J Cartledge and Graham Byrnes and Jiri Zavadil and Jing Su and Ivana Holcatova and Antonin Brisuda and David Zaridze and Anush Moukeria and Lenka Foretova and Marie Navratilova and Dana Mates and Viorel Jinga and Artem Artemov and Artem Nedoluzhko and Alexander Mazur and Sergey Rastorguev and Eugenia Boulygina and Simon Heath and Marta Gut and Marie-Therese Bihoreau and Doris Lechner and Mario Foglio and Ivo G Gut and Konstantin Skryabin and Egor Prokhortchouk and Anne Cambon-Thomsen and Johan Rung and Guillaume Bourque and Paul Brennan and Jörg Tost and Rosamonde E Banks and Alvis Brazma and G Mark Lathrop},

doi = {10.1038/ncomms6135},

issn = {2041-1723},

year  = {2014},

date = {2014-10-01},

journal = {Nat Commun},

volume = {5},

pages = {5135},

abstract = {The incidence of renal cell carcinoma (RCC) is increasing worldwide, and its prevalence is particularly high in some parts of Central Europe. Here we undertake whole-genome and transcriptome sequencing of clear cell RCC (ccRCC), the most common form of the disease, in patients from four different European countries with contrasting disease incidence to explore the underlying genomic architecture of RCC. Our findings support previous reports on frequent aberrations in the epigenetic machinery and PI3K/mTOR signalling, and uncover novel pathways and genes affected by recurrent mutations and abnormal transcriptome patterns including focal adhesion, components of extracellular matrix (ECM) and genes encoding FAT cadherins. Furthermore, a large majority of patients from Romania have an unexpected high frequency of A:T>T:A transversions, consistent with exposure to aristolochic acid (AA). These results show that the processes underlying ccRCC tumorigenesis may vary in different populations and suggest that AA may be an important ccRCC carcinogen in Romania, a finding with major public health implications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25268389,

title = {Mouse ENU Mutagenesis to Understand Immunity to Infection: Methods, Selected Examples, and Perspectives},

author = {Grégory Caignard and Megan M Eva and Rebekah van Bruggen and Robert Eveleigh and Guillaume Bourque and Danielle Malo and Philippe Gros and Silvia M Vidal},

doi = {10.3390/genes5040887},

issn = {2073-4425},

year  = {2014},

date = {2014-09-01},

journal = {Genes (Basel)},

volume = {5},

number = {4},

pages = {887--925},

abstract = {Infectious diseases are responsible for over 25% of deaths globally, but many more individuals are exposed to deadly pathogens. The outcome of infection results from a set of diverse factors including pathogen virulence factors, the environment, and the genetic make-up of the host. The completion of the human reference genome sequence in 2004 along with technological advances have tremendously accelerated and renovated the tools to study the genetic etiology of infectious diseases in humans and its best characterized mammalian model, the mouse. Advancements in mouse genomic resources have accelerated genome-wide functional approaches, such as gene-driven and phenotype-driven mutagenesis, bringing to the fore the use of mouse models that reproduce accurately many aspects of the pathogenesis of human infectious diseases. Treatment with the mutagen N-ethyl-N-nitrosourea (ENU) has become the most popular phenotype-driven approach. Our team and others have employed mouse ENU mutagenesis to identify host genes that directly impact susceptibility to pathogens of global significance. In this review, we first describe the strategies and tools used in mouse genetics to understand immunity to infection with special emphasis on chemical mutagenesis of the mouse germ-line together with current strategies to efficiently identify functional mutations using next generation sequencing. Then, we highlight illustrative examples of genes, proteins, and cellular signatures that have been revealed by ENU screens and have been shown to be involved in susceptibility or resistance to infectious diseases caused by parasites, bacteria, and viruses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25122610,

title = {Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation},

author = {Sandra Salem and David Langlais and François Lefebvre and Guillaume Bourque and Venetia Bigley and Muzz Haniffa and Jean-Laurent Casanova and David Burk and Albert Berghuis and Karina M Butler and Timothy Ronan Leahy and Sophie Hambleton and Philippe Gros},

doi = {10.1182/blood-2014-04-570879},

issn = {1528-0020},

year  = {2014},

date = {2014-09-01},

journal = {Blood},

volume = {124},

number = {12},

pages = {1894--1904},

abstract = {We have previously reported on a unique patient in whom homozygosity for a mutation at IRF8 (IRF8(K108E)) causes a severe immunodeficiency. Laboratory evaluation revealed a highly unusual myeloid compartment, remarkable for the complete absence of CD141 and CD161 monocytes, absence of CD11c1 conventional dendritic cells (DCs) and CD11c1/CD1231 plasmacytoid DCs, and striking granulocytic hyperplasia. The patient initially presented with severe disseminated mycobacterial and mucocutaneous fungal infections and was ultimately cured by cord blood transplant. Sequencing RNA from the IRF8(K108E) patient's primary blood cells prior to transplant shows not only depletion of IRF8-bound and IRF8-regulated transcriptional targets, in keeping with the distorted composition of the myeloid compartment, but also a paucity of transcripts associated with activated CD41 and CD81 T lymphocytes. This suggests that T cells reared in the absence of a functional antigen-presenting compartment in IRF8(K108E) are anergic. Biochemical characterization of the IRF8(K108E) mutant in vitro shows that loss of the positively charged side chain at K108 causes loss of nuclear localization and loss of transcriptional activity, which is concomitant with decreased protein stability, increased ubiquitination, increased small ubiquitin-like modification, and enhanced proteasomal degradation. These findings provide functional insight into the molecular basis of immunodeficiency associated with loss of IRF8.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24705254,

title = {Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations},

author = {Pawel Buczkowicz and Christine Hoeman and Patricia Rakopoulos and Sanja Pajovic and Louis Letourneau and Misko Dzamba and Andrew Morrison and Peter Lewis and Eric Bouffet and Ute Bartels and Jennifer Zuccaro and Sameer Agnihotri and Scott Ryall and Mark Barszczyk and Yevgen Chornenkyy and Mathieu Bourgey and Guillaume Bourque and Alexandre Montpetit and Francisco Cordero and Pedro Castelo-Branco and Joshua Mangerel and Uri Tabori and King Ching Ho and Annie Huang and Kathryn R Taylor and Alan Mackay and Anne E Bendel and Javad Nazarian and Jason R Fangusaro and Matthias A Karajannis and David Zagzag and Nicholas K Foreman and Andrew Donson and Julia V Hegert and Amy Smith and Jennifer Chan and Lucy Lafay-Cousin and Sandra Dunn and Juliette Hukin and Chris Dunham and Katrin Scheinemann and Jean Michaud and Shayna Zelcer and David Ramsay and Jason Cain and Cameron Brennan and Mark M Souweidane and Chris Jones and C David Allis and Michael Brudno and Oren Becher and Cynthia Hawkins},

doi = {10.1038/ng.2936},

issn = {1546-1718},

year  = {2014},

date = {2014-05-01},

journal = {Nat Genet},

volume = {46},

number = {5},

pages = {451--456},

abstract = {Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24681886,

title = {The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity},

author = {Xinyi Lu and Friedrich Sachs and LeeAnn Ramsay and Pierre-Étienne Jacques and Jonathan Göke and Guillaume Bourque and Huck-Hui Ng},

doi = {10.1038/nsmb.2799},

issn = {1545-9985},

year  = {2014},

date = {2014-04-01},

journal = {Nat Struct Mol Biol},

volume = {21},

number = {4},

pages = {423--425},

abstract = {Human endogenous retrovirus subfamily H (HERVH) is a class of transposable elements expressed preferentially in human embryonic stem cells (hESCs). Here, we report that the long terminal repeats of HERVH function as enhancers and that HERVH is a nuclear long noncoding RNA required to maintain hESC identity. Furthermore, HERVH is associated with OCT4, coactivators and Mediator subunits. Together, these results uncover a new role of species-specific transposable elements in hESCs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24520174,

title = {Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations},

author = {Nathalie Magnus and Delphine Garnier and Brian Meehan and Serge McGraw and Tae Hoon Lee and Maxime Caron and Guillaume Bourque and Chloe Milsom and Nada Jabado and Jacquetta Trasler and Rafal Pawlinski and Nigel Mackman and Janusz Rak},

doi = {10.1073/pnas.1314118111},

issn = {1091-6490},

year  = {2014},

date = {2014-03-01},

journal = {Proc Natl Acad Sci U S A},

volume = {111},

number = {9},

pages = {3544--3549},

abstract = {The coagulation system links immediate (hemostatic) and late (inflammatory, angiogenic) tissue responses to injury, a continuum that often is subverted in cancer. Here we provide evidence that tumor dormancy is influenced by tissue factor (TF), the cancer cell-associated initiator of the coagulation system and a signaling receptor. Thus, indolent human glioma cells deficient for TF remain viable but permanently dormant at the injection site for nearly a year, whereas the expression of TF leads to a step-wise transition to latent and overt tumor growth phases, a process that is preceded by recruitment of vascular (CD105(+)) and myeloid (CD11b(+) and F4/80(+)) cells. Importantly, the microenvironment orchestrated by TF expression drives permanent changes in the phenotype, gene-expression profile, DNA copy number, and DNA methylation state of the tumor cells that escape from dormancy. We postulate that procoagulant events in the tissue microenvironment (niche) may affect the fate of occult tumor cells, including their biological and genetic progression to initiate a full-blown malignancy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24013217,

title = {SON connects the splicing-regulatory network with pluripotency in human embryonic stem cells},

author = {Xinyi Lu and Jonathan Göke and Friedrich Sachs and Pierre-Étienne Jacques and Hongqing Liang and Bo Feng and Guillaume Bourque and Paula A Bubulya and Huck-Hui Ng},

doi = {10.1038/ncb2839},

issn = {1476-4679},

year  = {2013},

date = {2013-10-01},

journal = {Nat Cell Biol},

volume = {15},

number = {10},

pages = {1141--1152},

abstract = {Human embryonic stem cells (hESCs) harbour the ability to undergo lineage-specific differentiation into clinically relevant cell types. Transcription factors and epigenetic modifiers are known to play important roles in the maintenance of pluripotency of hESCs. However, little is known about regulation of pluripotency through splicing. In this study, we identify the spliceosome-associated factor SON as a factor essential for the maintenance of hESCs. Depletion of SON in hESCs results in the loss of pluripotency and cell death. Using genome-wide RNA profiling, we identified transcripts that are regulated by SON. Importantly, we confirmed that SON regulates the proper splicing of transcripts encoding for pluripotency regulators such as OCT4, PRDM14, E4F1 and MED24. Furthermore, we show that SON is bound to these transcripts in vivo. In summary, we connect a splicing-regulatory network for accurate transcript production to the maintenance of pluripotency and self-renewal of hESCs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23675311,

title = {The majority of primate-specific regulatory sequences are derived from transposable elements},

author = {Pierre-Étienne Jacques and Justin Jeyakani and Guillaume Bourque},

doi = {10.1371/journal.pgen.1003504},

issn = {1553-7404},

year  = {2013},

date = {2013-05-01},

journal = {PLoS Genet},

volume = {9},

number = {5},

pages = {e1003504},

abstract = {Although emerging evidence suggests that transposable elements (TEs) have contributed novel regulatory elements to the human genome, their global impact on transcriptional networks remains largely uncharacterized. Here we show that TEs have contributed to the human genome nearly half of its active elements. Using DNase I hypersensitivity data sets from ENCODE in normal, embryonic, and cancer cells, we found that 44% of open chromatin regions were in TEs and that this proportion reached 63% for primate-specific regions. We also showed that distinct subfamilies of endogenous retroviruses (ERVs) contributed significantly more accessible regions than expected by chance, with up to 80% of their instances in open chromatin. Based on these results, we further characterized 2,150 TE subfamily-transcription factor pairs that were bound in vivo or enriched for specific binding motifs, and observed that TEs contributing to open chromatin had higher levels of sequence conservation. We also showed that thousands of ERV-derived sequences were activated in a cell type-specific manner, especially in embryonic and cancer cells, and we demonstrated that this activity was associated with cell type-specific expression of neighboring genes. Taken together, these results demonstrate that TEs, and in particular ERVs, have contributed hundreds of thousands of novel regulatory elements to the primate lineage and reshaped the human transcriptional landscape.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23637635,

title = {Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs},

author = {Aurélie Kapusta and Zev Kronenberg and Vincent J Lynch and Xiaoyu Zhuo and LeeAnn Ramsay and Guillaume Bourque and Mark Yandell and Cédric Feschotte},

doi = {10.1371/journal.pgen.1003470},

issn = {1553-7404},

year  = {2013},

date = {2013-04-01},

journal = {PLoS Genet},

volume = {9},

number = {4},

pages = {e1003470},

abstract = {Advances in vertebrate genomics have uncovered thousands of loci encoding long noncoding RNAs (lncRNAs). While progress has been made in elucidating the regulatory functions of lncRNAs, little is known about their origins and evolution. Here we explore the contribution of transposable elements (TEs) to the makeup and regulation of lncRNAs in human, mouse, and zebrafish. Surprisingly, TEs occur in more than two thirds of mature lncRNA transcripts and account for a substantial portion of total lncRNA sequence (~30% in human), whereas they seldom occur in protein-coding transcripts. While TEs contribute less to lncRNA exons than expected, several TE families are strongly enriched in lncRNAs. There is also substantial interspecific variation in the coverage and types of TEs embedded in lncRNAs, partially reflecting differences in the TE landscapes of the genomes surveyed. In human, TE sequences in lncRNAs evolve under greater evolutionary constraint than their non-TE sequences, than their intronic TEs, or than random DNA. Consistent with functional constraint, we found that TEs contribute signals essential for the biogenesis of many lncRNAs, including ~30,000 unique sites for transcription initiation, splicing, or polyadenylation in human. In addition, we identified ~35,000 TEs marked as open chromatin located within 10 kb upstream of lncRNA genes. The density of these marks in one cell type correlate with elevated expression of the downstream lncRNA in the same cell type, suggesting that these TEs contribute to cis-regulation. These global trends are recapitulated in several lncRNAs with established functions. Finally a subset of TEs embedded in lncRNAs are subject to RNA editing and predicted to form secondary structures likely important for function. In conclusion, TEs are nearly ubiquitous in lncRNAs and have played an important role in the lineage-specific diversification of vertebrate lncRNA repertoires.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23562079,

title = {Molecular and genetic crosstalks between mTOR and ERRα are key determinants of rapamycin-induced nonalcoholic fatty liver},

author = {Cédric Chaveroux and Lillian J Eichner and Catherine R Dufour and Aymen Shatnawi and Arkady Khoutorsky and Guillaume Bourque and Nahum Sonenberg and Vincent Giguère},

doi = {10.1016/j.cmet.2013.03.003},

issn = {1932-7420},

year  = {2013},

date = {2013-04-01},

journal = {Cell Metab},

volume = {17},

number = {4},

pages = {586--598},

abstract = {mTOR and ERRα are key regulators of common metabolic processes, including lipid homeostasis. However, it is currently unknown whether these factors cooperate in the control of metabolism. ChIP-sequencing analyses of mouse liver reveal that mTOR occupies regulatory regions of genes on a genome-wide scale including enrichment at genes shared with ERRα that are involved in the TCA cycle and lipid biosynthesis. Genetic ablation of ERRα and rapamycin treatment, alone or in combination, alter the expression of these genes and induce the accumulation of TCA metabolites. As a consequence, both genetic and pharmacological inhibition of ERRα activity exacerbates hepatic hyperlipidemia observed in rapamycin-treated mice. We further show that mTOR regulates ERRα activity through ubiquitin-mediated degradation via transcriptional control of the ubiquitin-proteasome pathway. Our work expands the role of mTOR action in metabolism and highlights the existence of a potent mTOR/ERRα regulatory axis with significant clinical impact.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23237666,

title = {Whole-genome reconstruction and mutational signatures in gastric cancer},

author = {Niranjan Nagarajan and Denis Bertrand and Axel M Hillmer and Zhi Jiang Zang and Fei Yao and Pierre-Étienne Jacques and Audrey S M Teo and Ioana Cutcutache and Zhenshui Zhang and Wah Heng Lee and Yee Yen Sia and Song Gao and Pramila N Ariyaratne and Andrea Ho and Xing Yi Woo and Lavanya Veeravali and Choon Kiat Ong and Niantao Deng and Kartiki V Desai and Chiea Chuen Khor and Martin L Hibberd and Atif Shahab and Jaideepraj Rao and Mengchu Wu and Ming Teh and Feng Zhu and Sze Yung Chin and Brendan Pang and Jimmy B Y So and Guillaume Bourque and Richie Soong and Wing-Kin Sung and Bin Tean Teh and Steven Rozen and Xiaoan Ruan and Khay Guan Yeoh and Patrick B O Tan and Yijun Ruan},

doi = {10.1186/gb-2012-13-12-r115},

issn = {1474-760X},

year  = {2012},

date = {2012-12-01},

journal = {Genome Biol},

volume = {13},

number = {12},

pages = {R115},

abstract = {BACKGROUND: Gastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability.



RESULTS: Integrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer--against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer.



CONCLUSIONS: These results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22661320,

title = {K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas},

author = {Dong-Anh Khuong-Quang and Pawel Buczkowicz and Patricia Rakopoulos and Xiao-Yang Liu and Adam M Fontebasso and Eric Bouffet and Ute Bartels and Steffen Albrecht and Jeremy Schwartzentruber and Louis Letourneau and Mathieu Bourgey and Guillaume Bourque and Alexandre Montpetit and Genevieve Bourret and Pierre Lepage and Adam Fleming and Peter Lichter and Marcel Kool and Andreas von Deimling and Dominik Sturm and Andrey Korshunov and Damien Faury and David T Jones and Jacek Majewski and Stefan M Pfister and Nada Jabado and Cynthia Hawkins},

doi = {10.1007/s00401-012-0998-0},

issn = {1432-0533},

year  = {2012},

date = {2012-09-01},

journal = {Acta Neuropathol},

volume = {124},

number = {3},

pages = {439--447},

abstract = {Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22308434,

title = {Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors},

author = {Emilie A Bard-Chapeau and Justin Jeyakani and Chung H Kok and Julius Muller and Belinda Q Chua and Jayantha Gunaratne and Arsen Batagov and Piroon Jenjaroenpun and Vladimir A Kuznetsov and Chia-Lin Wei and Richard J D'Andrea and Guillaume Bourque and Nancy A Jenkins and Neal G Copeland},

doi = {10.1073/pnas.1119229109},

issn = {1091-6490},

year  = {2012},

date = {2012-02-01},

journal = {Proc Natl Acad Sci U S A},

volume = {109},

number = {6},

pages = {2168--2173},

abstract = {Ecotropic viral integration site 1 (EVI1) is an oncogenic dual domain zinc finger transcription factor that plays an essential role in the regulation of hematopoietic stem cell renewal, and its overexpression in myeloid leukemia and epithelial cancers is associated with poor patient survival. Despite the discovery of EVI1 in 1988 and its emerging role as a dominant oncogene in various types of cancer, few EVI1 target genes are known. This lack of knowledge has precluded a clear understanding of exactly how EVI1 contributes to cancer. Using a combination of ChIP-Seq and microarray studies in human ovarian carcinoma cells, we show that the two zinc finger domains of EVI1 bind to DNA independently and regulate different sets of target genes. Strikingly, an enriched fraction of EVI1 target genes are cancer genes or genes associated with cancer. We also show that more than 25% of EVI1-occupied genes contain linked EVI1 and activator protein (AP)1 DNA binding sites, and this finding provides evidence for a synergistic cooperative interaction between EVI1 and the AP1 family member FOS in the regulation of cell adhesion, proliferation, and colony formation. An increased number of dual EVI1/AP1 target genes are also differentially regulated in late-stage ovarian carcinomas, further confirming the importance of the functional cooperation between EVI1 and FOS. Collectively, our data indicate that EVI1 is a multipurpose transcription factor that synergizes with FOS in invasive tumors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23118933,

title = {PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse},

author = {Sebastian Pott and Nima K Kamrani and Guillaume Bourque and Sven Pettersson and Edison T Liu},

doi = {10.1371/journal.pone.0048102},

issn = {1932-6203},

year  = {2012},

date = {2012-01-01},

journal = {PLoS One},

volume = {7},

number = {10},

pages = {e48102},

abstract = {BACKGROUND: Genome-wide comparisons of transcription factor binding sites in different species can be used to evaluate evolutionary constraints that shape gene regulatory circuits and to understand how the interaction between transcription factors shapes their binding landscapes over evolution.



RESULTS: We have compared the PPARG binding landscapes in macrophages to investigate the evolutionary impact on PPARG binding diversity in mouse and humans for this important nuclear receptor. Of note, only 5% of the PPARG binding sites were shared between the two species. In contrast, at the gene level, PPARG target genes conserved between both species constitute more than 30% of the target genes regulated by PPARG ligand in human macrophages. Moreover, the majority of all PPARG binding sites (55-60%) in macrophages show co-occupancy of the lineage-specification factor PU.1 in both species. Exploring the evolutionary dynamics of PPARG binding sites, we observed that PU.1 co-binding to PPARG sites appears to be important for possible PPARG ancestral functions such as lipid metabolism. Thus we speculate that PU.1 may have guided utilization of these species-specific PPARG conserved binding sites in macrophages during evolution.



CONCLUSIONS: We propose a model in which PU.1 sites may have served as "anchor" loci for the formation of new and functionally relevant PPARG binding sites throughout evolution. As PU.1 is an essential factor in macrophage biology, such an evolutionary mechanism would allow for the establishment of relevant PPARG regulatory modules in a PU.1-dependent manner and yet permit for nuanced regulatory changes in individual species.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23029419,

title = {Long span DNA paired-end-tag (DNA-PET) sequencing strategy for the interrogation of genomic structural mutations and fusion-point-guided reconstruction of amplicons},

author = {Fei Yao and Pramila N Ariyaratne and Axel M Hillmer and Wah Heng Lee and Guoliang Li and Audrey S M Teo and Xing Yi Woo and Zhenshui Zhang and Jieqi P Chen and Wan Ting Poh and Kelson F B Zawack and Chee Seng Chan and See Ting Leong and Say Chuan Neo and Poh Sum D Choi and Song Gao and Niranjan Nagarajan and Hervé Thoreau and Atif Shahab and Xiaoan Ruan and Valère Cacheux-Rataboul and Chia-Lin Wei and Guillaume Bourque and Wing-Kin Sung and Edison T Liu and Yijun Ruan},

doi = {10.1371/journal.pone.0046152},

issn = {1932-6203},

year  = {2012},

date = {2012-01-01},

journal = {PLoS One},

volume = {7},

number = {9},

pages = {e46152},

abstract = {Structural variations (SVs) contribute significantly to the variability of the human genome and extensive genomic rearrangements are a hallmark of cancer. While genomic DNA paired-end-tag (DNA-PET) sequencing is an attractive approach to identify genomic SVs, the current application of PET sequencing with short insert size DNA can be insufficient for the comprehensive mapping of SVs in low complexity and repeat-rich genomic regions. We employed a recently developed procedure to generate PET sequencing data using large DNA inserts of 10-20 kb and compared their characteristics with short insert (1 kb) libraries for their ability to identify SVs. Our results suggest that although short insert libraries bear an advantage in identifying small deletions, they do not provide significantly better breakpoint resolution. In contrast, large inserts are superior to short inserts in providing higher physical genome coverage for the same sequencing cost and achieve greater sensitivity, in practice, for the identification of several classes of SVs, such as copy number neutral and complex events. Furthermore, our results confirm that large insert libraries allow for the identification of SVs within repetitive sequences, which cannot be spanned by short inserts. This provides a key advantage in studying rearrangements in cancer, and we show how it can be used in a fusion-point-guided-concatenation algorithm to study focally amplified regions in cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22011226,

title = {Conserved and non-conserved enhancers direct tissue specific transcription in ancient germ layer specific developmental control genes},

author = {Sumantra Chatterjee and Guillaume Bourque and Thomas Lufkin},

doi = {10.1186/1471-213X-11-63},

issn = {1471-213X},

year  = {2011},

date = {2011-10-01},

journal = {BMC Dev Biol},

volume = {11},

pages = {63},

abstract = {BACKGROUND: Identifying DNA sequences (enhancers) that direct the precise spatial and temporal expression of developmental control genes remains a significant challenge in the annotation of vertebrate genomes. Locating these sequences, which in many cases lie at a great distance from the transcription start site, has been a major obstacle in deciphering gene regulation. Coupling of comparative genomics with functional validation to locate such regulatory elements has been a successful method in locating many such regulatory elements. But most of these studies looked either at a single gene only or the whole genome without focusing on any particular process. The pressing need is to integrate the tools of comparative genomics with knowledge of developmental biology to validate enhancers for developmental transcription factors in greater detail



RESULTS: Our results show that near four different genes (nkx3.2, pax9, otx1b and foxa2) in zebrafish, only 20-30% of highly conserved DNA sequences can act as developmental enhancers irrespective of the tissue the gene expresses in. We find that some genes also have multiple conserved enhancers expressing in the same tissue at the same or different time points in development. We also located non-conserved enhancers for two of the genes (pax9 and otx1b). Our modified Bacterial artificial chromosome (BACs) studies for these 4 genes revealed that many of these enhancers work in a synergistic fashion, which cannot be captured by individual DNA constructs and are not conserved at the sequence level. Our detailed biochemical and transgenic analysis revealed Foxa1 binds to the otx1b non-conserved enhancer to direct its activity in forebrain and otic vesicle of zebrafish at 24 hpf.



CONCLUSION: Our results clearly indicate that high level of functional conservation of genes is not necessarily associated with sequence conservation of its regulatory elements. Moreover certain non conserved DNA elements might have role in gene regulation. The need is to bring together multiple approaches to bear upon individual genes to decipher all its regulatory elements.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid21555364b,

title = {Zebrafish mRNA sequencing deciphers novelties in transcriptome dynamics during maternal to zygotic transition},

author = {Håvard Aanes and Cecilia L Winata and Chi Ho Lin and Jieqi P Chen and Kandhadayar G Srinivasan and Serene G P Lee and Adrian Y M Lim and Hajira Shreen Hajan and Philippe Collas and Guillaume Bourque and Zhiyuan Gong and Vladimir Korzh and Peter Aleström and Sinnakaruppan Mathavan},

doi = {10.1101/gr.116012.110},

issn = {1549-5469},

year  = {2011},

date = {2011-08-01},

journal = {Genome Res},

volume = {21},

number = {8},

pages = {1328--1338},

abstract = {Maternally deposited mRNAs direct early development before the initiation of zygotic transcription during mid-blastula transition (MBT). To study mechanisms regulating this developmental event in zebrafish, we applied mRNA deep sequencing technology and generated comprehensive information and valuable resources on transcriptome dynamics during early embryonic (egg to early gastrulation) stages. Genome-wide transcriptome analysis documented at least 8000 maternal genes and identified the earliest cohort of zygotic transcripts. We determined expression levels of maternal and zygotic transcripts with the highest resolution possible using mRNA-seq and clustered them based on their expression pattern. We unravel delayed polyadenylation in a large cohort of maternal transcripts prior to the MBT for the first time in zebrafish. Blocking polyadenylation of these transcripts confirms their role in regulating development from the MBT onward. Our study also identified a large number of novel transcribed regions in annotated and unannotated regions of the genome, which will facilitate reannotation of the zebrafish genome. We also identified splice variants with an estimated frequency of 50%-60%. Taken together, our data constitute a useful genomic information and valuable transcriptome resource for gene discovery and for understanding the mechanisms of early embryogenesis in zebrafish.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid21685913,

title = {CTCF-mediated functional chromatin interactome in pluripotent cells},

author = {Lusy Handoko and Han Xu and Guoliang Li and Chew Yee Ngan and Elaine Chew and Marie Schnapp and Charlie Wah Heng Lee and Chaopeng Ye and Joanne Lim Hui Ping and Fabianus Mulawadi and Eleanor Wong and Jianpeng Sheng and Yubo Zhang and Thompson Poh and Chee Seng Chan and Galih Kunarso and Atif Shahab and Guillaume Bourque and Valere Cacheux-Rataboul and Wing-Kin Sung and Yijun Ruan and Chia-Lin Wei},

doi = {10.1038/ng.857},

issn = {1546-1718},

year  = {2011},

date = {2011-06-01},

journal = {Nat Genet},

volume = {43},

number = {7},

pages = {630--638},

abstract = {Mammalian genomes are viewed as functional organizations that orchestrate spatial and temporal gene regulation. CTCF, the most characterized insulator-binding protein, has been implicated as a key genome organizer. However, little is known about CTCF-associated higher-order chromatin structures at a global scale. Here we applied chromatin interaction analysis by paired-end tag (ChIA-PET) sequencing to elucidate the CTCF-chromatin interactome in pluripotent cells. From this analysis, we identified 1,480 cis- and 336 trans-interacting loci with high reproducibility and precision. Associating these chromatin interaction loci with their underlying epigenetic states, promoter activities, enhancer binding and nuclear lamina occupancy, we uncovered five distinct chromatin domains that suggest potential new models of CTCF function in chromatin organization and transcriptional control. Specifically, CTCF interactions demarcate chromatin-nuclear membrane attachments and influence proper gene expression through extensive cross-talk between promoters and regulatory elements. This highly complex nuclear organization offers insights toward the unifying principles that govern genome plasticity and function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid21467267b,

title = {Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes},

author = {Axel M Hillmer and Fei Yao and Koichiro Inaki and Wah Heng Lee and Pramila N Ariyaratne and Audrey S M Teo and Xing Yi Woo and Zhenshui Zhang and Hao Zhao and Leena Ukil and Jieqi P Chen and Feng Zhu and Jimmy B Y So and Manuel Salto-Tellez and Wan Ting Poh and Kelson F B Zawack and Niranjan Nagarajan and Song Gao and Guoliang Li and Vikrant Kumar and Hui Ping J Lim and Yee Yen Sia and Chee Seng Chan and See Ting Leong and Say Chuan Neo and Poh Sum D Choi and Hervé Thoreau and Patrick B O Tan and Atif Shahab and Xiaoan Ruan and Jonas Bergh and Per Hall and Valère Cacheux-Rataboul and Chia-Lin Wei and Khay Guan Yeoh and Wing-Kin Sung and Guillaume Bourque and Edison T Liu and Yijun Ruan},

doi = {10.1101/gr.113555.110},

issn = {1549-5469},

year  = {2011},

date = {2011-05-01},

journal = {Genome Res},

volume = {21},

number = {5},

pages = {665--675},

abstract = {Somatic genome rearrangements are thought to play important roles in cancer development. We optimized a long-span paired-end-tag (PET) sequencing approach using 10-Kb genomic DNA inserts to study human genome structural variations (SVs). The use of a 10-Kb insert size allows the identification of breakpoints within repetitive or homology-containing regions of a few kilobases in size and results in a higher physical coverage compared with small insert libraries with the same sequencing effort. We have applied this approach to comprehensively characterize the SVs of 15 cancer and two noncancer genomes and used a filtering approach to strongly enrich for somatic SVs in the cancer genomes. Our analyses revealed that most inversions, deletions, and insertions are germ-line SVs, whereas tandem duplications, unpaired inversions, interchromosomal translocations, and complex rearrangements are over-represented among somatic rearrangements in cancer genomes. We demonstrate that the quantitative and connective nature of DNA-PET data is precise in delineating the genealogy of complex rearrangement events, we observe signatures that are compatible with breakage-fusion-bridge cycles, and we discover that large duplications are among the initial rearrangements that trigger genome instability for extensive amplification in epithelial cancers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid21467264b,

title = {Transcriptional consequences of genomic structural aberrations in breast cancer},

author = {Koichiro Inaki and Axel M Hillmer and Leena Ukil and Fei Yao and Xing Yi Woo and Leah A Vardy and Kelson Folkvard Braaten Zawack and Charlie Wah Heng Lee and Pramila Nuwantha Ariyaratne and Yang Sun Chan and Kartiki Vasant Desai and Jonas Bergh and Per Hall and Thomas Choudary Putti and Wai Loon Ong and Atif Shahab and Valere Cacheux-Rataboul and Radha Krishna Murthy Karuturi and Wing-Kin Sung and Xiaoan Ruan and Guillaume Bourque and Yijun Ruan and Edison T Liu},

doi = {10.1101/gr.113225.110},

issn = {1549-5469},

year  = {2011},

date = {2011-05-01},

journal = {Genome Res},

volume = {21},

number = {5},

pages = {676--687},

abstract = {Using a long-span, paired-end deep sequencing strategy, we have comprehensively identified cancer genome rearrangements in eight breast cancer genomes. Herein, we show that 40%-54% of these structural genomic rearrangements result in different forms of fusion transcripts and that 44% are potentially translated. We find that single segmental tandem duplication spanning several genes is a major source of the fusion gene transcripts in both cell lines and primary tumors involving adjacent genes placed in the reverse-order position by the duplication event. Certain other structural mutations, however, tend to attenuate gene expression. From these candidate gene fusions, we have found a fusion transcript (RPS6KB1-VMP1) recurrently expressed in ∼30% of breast cancers associated with potential clinical consequences. This gene fusion is caused by tandem duplication on 17q23 and appears to be an indicator of local genomic instability altering the expression of oncogenic components such as MIR21 and RPS6KB1.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid21575170,

title = {Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines},

author = {Siew Hong Lam and Serene G P Lee and Chin Y Lin and Jane S Thomsen and Pan Y Fu and Karuturi R K Murthy and Haixia Li and Kunde R Govindarajan and Lin C H Nick and Guillaume Bourque and Zhiyuan Gong and Thomas Lufkin and Edison T Liu and Sinnakaruppan Mathavan},

doi = {10.1186/1755-8794-4-41},

issn = {1755-8794},

year  = {2011},

date = {2011-05-01},

journal = {BMC Med Genomics},

volume = {4},

pages = {41},

abstract = {BACKGROUND: The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines.



METHODS: Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen) and an anti-estrogen (ICI 182,780). Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa).



RESULTS: Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE), is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry points for estrogen regulation.



CONCLUSION: The findings demonstrate the use of zebrafish for characterizing estrogen-like environmental carcinogens and anti-estrogen drug screening. From an evolutionary perspective, our findings suggest that estrogen regulation of cell cycle is perhaps one of the earliest forms of steroidal-receptor controlled cellular processes. Our study provides first evidence of molecular conservation of estrogen-responsiveness between zebrafish and human cancer cell lines, hence demonstrating the potential of zebrafish for estrogen-related cancer research.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid21569470,

title = {In silico tandem affinity purification refines an Oct4 interaction list},

author = {Clara Yujing Cheong and Patricia Miang Lon Ng and Rhonda Ponnampalam and Heng-Hang Tsai and Guillaume Bourque and Thomas Lufkin},

doi = {10.1186/scrt67},

issn = {1757-6512},

year  = {2011},

date = {2011-05-01},

journal = {Stem Cell Res Ther},

volume = {2},

number = {3},

pages = {26},

abstract = {INTRODUCTION: Octamer-binding transcription factor 4 (Oct4) is a master regulator of early mammalian development. Its expression begins from the oocyte stage, becomes restricted to the inner cell mass of the blastocyst and eventually remains only in primordial germ cells. Unearthing the interactions of Oct4 would provide insight into how this transcription factor is central to cell fate and stem cell pluripotency.



METHODS: In the present study, affinity-tagged endogenous Oct4 cell lines were established via homologous recombination gene targeting in embryonic stem (ES) cells to express tagged Oct4. This allows tagged Oct4 to be expressed without altering the total Oct4 levels from their physiological levels.



RESULTS: Modified ES cells remained pluripotent. However, when modified ES cells were tested for their functionality, cells with a large tag failed to produce viable homozygous mice. Use of a smaller tag resulted in mice with normal development, viability and fertility. This indicated that the choice of tags can affect the performance of Oct4. Also, different tags produce a different repertoire of Oct4 interactors.



CONCLUSIONS: Using a total of four different tags, we found 33 potential Oct4 interactors, of which 30 are novel. In addition to transcriptional regulation, the molecular function associated with these Oct4-associated proteins includes various other catalytic activities, suggesting that, aside from chromosome remodeling and transcriptional regulation, Oct4 function extends more widely to other essential cellular mechanisms. Our findings show that multiple purification approaches are needed to uncover a comprehensive Oct4 protein interaction network.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22016335,

title = {CpG deamination creates transcription factor-binding sites with high efficiency},

author = {Tomasz Zemojtel and Szymon M Kielbasa and Peter F Arndt and Sarah Behrens and Guillaume Bourque and Martin Vingron},

doi = {10.1093/gbe/evr107},

issn = {1759-6653},

year  = {2011},

date = {2011-01-01},

journal = {Genome Biol Evol},

volume = {3},

pages = {1304--1311},

abstract = {The formation of new transcription factor-binding sites (TFBSs) has a major impact on the evolution of gene regulatory networks. Clearly, single nucleotide mutations arising within genomic DNA can lead to the creation of TFBSs. Are molecular processes inducing single nucleotide mutations contributing equally to the creation of TFBSs? In the human genome, a spontaneous deamination of methylated cytosine in the context of CpG dinucleotides results in the creation of thymine (C → T), and this mutation has the highest rate among all base substitutions. CpG deamination has been ascribed a role in silencing of transposons and induction of variation in regional methylation. We have previously shown that CpG deamination created thousands of p53-binding sites within genomic sequences of Alu transposons. Interestingly, we have defined a ∼30 bp region in Alu sequence, which, depending on a pattern of CpG deamination, can be converted to functional p53-, PAX-6-, and Myc-binding sites. Here, we have studied single nucleotide mutational events leading to creation of TFBSs in promoters of human genes and in genomic regions bound by such key transcription factors as Oct4, NANOG, and c-Myc. We document that CpG deamination events can create TFBSs with much higher efficiency than other types of mutational events. Our findings add a new role to CpG methylation: We propose that deamination of methylated CpGs constitutes one of the evolutionary forces acting on mutational trajectories of TFBSs formation contributing to variability in gene regulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid20526341b,

title = {Transposable elements have rewired the core regulatory network of human embryonic stem cells},

author = {Galih Kunarso and Na-Yu Chia and Justin Jeyakani and Catalina Hwang and Xinyi Lu and Yun-Shen Chan and Huck-Hui Ng and Guillaume Bourque},

doi = {10.1038/ng.600},

issn = {1546-1718},

year  = {2010},

date = {2010-07-01},

journal = {Nat Genet},

volume = {42},

number = {7},

pages = {631--634},

abstract = {Detection of new genomic control elements is critical in understanding transcriptional regulatory networks in their entirety. We studied the genome-wide binding locations of three key regulatory proteins (POU5F1, also known as OCT4; NANOG; and CTCF) in human and mouse embryonic stem cells. In contrast to CTCF, we found that the binding profiles of OCT4 and NANOG are markedly different, with only approximately 5% of the regions being homologously occupied. We show that transposable elements contributed up to 25% of the bound sites in humans and mice and have wired new genes into the core regulatory network of embryonic stem cells. These data indicate that species-specific transposable elements have substantially altered the transcriptional circuitry of pluripotent stem cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid20022974b,

title = {webMGR: an online tool for the multiple genome rearrangement problem},

author = {Chi Ho Lin and Hao Zhao and Sean Harry Lowcay and Atif Shahab and Guillaume Bourque},

doi = {10.1093/bioinformatics/btp689},

issn = {1367-4811},

year  = {2010},

date = {2010-02-01},

journal = {Bioinformatics},

volume = {26},

number = {3},

pages = {408--410},

abstract = {SUMMARY: The algorithm MGR enables the reconstruction of rearrangement phylogenies based on gene or synteny block order in multiple genomes. Although MGR has been successfully applied to study the evolution of different sets of species, its utilization has been hampered by the prohibitive running time for some applications. In the current work, we have designed new heuristics that significantly speed up the tool without compromising its accuracy. Moreover, we have developed a web server (webMGR) that includes elaborate web output to facilitate navigation through the results.



AVAILABILITY: webMGR can be accessed via http://www.gis.a-star.edu.sg/~bourque. The source code of the improved standalone version of MGR is also freely available from the web site.



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

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid20126276b,

title = {Success in the DREAM3 signaling response challenge using simple weighted-average imputation: lessons for community-wide experiments in systems biology},

author = {Neil D Clarke and Guillaume Bourque},

doi = {10.1371/journal.pone.0008417},

issn = {1932-6203},

year  = {2010},

date = {2010-01-01},

journal = {PLoS One},

volume = {5},

number = {1},

pages = {e8417},

abstract = {Our group produced the best predictions overall in the DREAM3 signaling response challenge, being tops by a substantial margin in the cytokine sub-challenge and nearly tied for best in the phosphoprotein sub-challenge. We achieved this success using a simple interpolation strategy. For each combination of a stimulus and inhibitor for which predictions were required, we had noted there were six other datasets using the same stimulus (but different inhibitor treatments) and six other datasets using the same inhibitor (but different stimuli). Therefore, for each treatment combination for which values were to be predicted, we calculated rank correlations for the data that were in common between the treatment combination and each of the 12 related combinations. The data from the 12 related combinations were then used to calculate missing values, weighting the contributions from each experiment based on the rank correlation coefficients. The success of this simple method suggests that the missing data were largely over-determined by similarities in the treatments. We offer some thoughts on the current state and future development of DREAM that are based on our success in this challenge, our success in the earlier DREAM2 transcription factor target challenge, and our experience as the data provider for the gene expression challenge in DREAM3.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid19914058b,

title = {Transposable elements in gene regulation and in the evolution of vertebrate genomes},

author = {Guillaume Bourque},

doi = {10.1016/j.gde.2009.10.013},

issn = {1879-0380},

year  = {2009},

date = {2009-12-01},

journal = {Curr Opin Genet Dev},

volume = {19},

number = {6},

pages = {607--612},

abstract = {Repetitive DNA and in particular transposable elements have been intimately linked to eukaryotic genomes for millions of years. Once overlooked for being only a collection of selfish debris and a nuisance for sequence assembly, genomic repeats are now being recognized as a key driving force in genome evolution. Indeed, by changing the DNA landscape of genomes, transposable elements have been a rich source of innovation in genes, regulatory elements and genome structures. In this review, I will focus on recent advances that demonstrate that genomic repeats have had a global impact on vertebrate gene regulatory networks. I will also summarize results that show how transposable elements have been a major catalyst of structural rearrangements throughout evolution.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid19890323b,

title = {An oestrogen-receptor-alpha-bound human chromatin interactome},

author = {Melissa J Fullwood and Mei Hui Liu and You Fu Pan and Jun Liu and Han Xu and Yusoff Bin Mohamed and Yuriy L Orlov and Stoyan Velkov and Andrea Ho and Poh Huay Mei and Elaine G Y Chew and Phillips Yao Hui Huang and Willem-Jan Welboren and Yuyuan Han and Hong Sain Ooi and Pramila N Ariyaratne and Vinsensius B Vega and Yanquan Luo and Peck Yean Tan and Pei Ye Choy and K D Senali Abayratna Wansa and Bing Zhao and Kar Sian Lim and Shi Chi Leow and Jit Sin Yow and Roy Joseph and Haixia Li and Kartiki V Desai and Jane S Thomsen and Yew Kok Lee and R Krishna Murthy Karuturi and Thoreau Herve and Guillaume Bourque and Hendrik G Stunnenberg and Xiaoan Ruan and Valere Cacheux-Rataboul and Wing-Kin Sung and Edison T Liu and Chia-Lin Wei and Edwin Cheung and Yijun Ruan},

doi = {10.1038/nature08497},

issn = {1476-4687},

year  = {2009},

date = {2009-11-01},

journal = {Nature},

volume = {462},

number = {7269},

pages = {58--64},

abstract = {Genomes are organized into high-level three-dimensional structures, and DNA elements separated by long genomic distances can in principle interact functionally. Many transcription factors bind to regulatory DNA elements distant from gene promoters. Although distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner. Here we describe the development of a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global chromatin interactions, with which we have comprehensively mapped the chromatin interaction network bound by oestrogen receptor alpha (ER-alpha) in the human genome. We found that most high-confidence remote ER-alpha-binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ER-alpha functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation. We propose that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid19411607b,

title = {Recovering genome rearrangements in the mammalian phylogeny},

author = {Hao Zhao and Guillaume Bourque},

doi = {10.1101/gr.086009.108},

issn = {1088-9051},

year  = {2009},

date = {2009-05-01},

journal = {Genome Res},

volume = {19},

number = {5},

pages = {934--942},

abstract = {The analysis of genome rearrangements provides a global view on the evolution of a set of related species. We present a new algorithm called EMRAE (efficient method to recover ancestral events) to reliably predict a wide-range of rearrangement events in the ancestry of a group of species. Using simulated data sets, we show that EMRAE achieves comparable sensitivity but significantly higher specificity when predicting evolutionary events relative to other tools to study genome rearrangements. We apply our approach to the synteny blocks of six mammalian genomes (human, chimpanzee, rhesus macaque, mouse, rat, and dog) and predict 1109 rearrangement events, including 831 inversions, 15 translocations, 237 transpositions, and 26 fusions/fissions. Studying the sequence features at the breakpoints of the primate rearrangement events, we demonstrate that they are not only enriched in segmental duplications (SDs), but that the enrichment of matching pairs of SDs is even stronger within the pairs of breakpoints associated with recovered events. We also show that pairs of L1 repeats are frequently associated with ancestral inversions across all studied lineages. Together, this substantiates the model that regions of high sequence identity have been associated with rearrangement events throughout the mammalian phylogeny.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid19348643b,

title = {Inferring direct regulatory targets of a transcription factor in the DREAM2 challenge},

author = {Vinsensius B Vega and Xing Yi Woo and Habib Hamidi and Hock Chuan Yeo and Zhen Xuan Yeo and Guillaume Bourque and Neil D Clarke},

doi = {10.1111/j.1749-6632.2008.03759.x},

issn = {1749-6632},

year  = {2009},

date = {2009-03-01},

journal = {Ann N Y Acad Sci},

volume = {1158},

pages = {215--223},

abstract = {In the DREAM2 community-wide experiment on regulatory network inference, one of the challenges was to identify which genes, in a list of 200, are direct regulatory targets of the transcription factor BCL6. The organizers of the challenge defined targets based on gene expression and chromatin immunoprecipitation experiments (ChIP-chip). The expression data were publicly available; the ChIP-chip data were not. In order to assess the likelihood that a gene is a BCL6 target, we used three classes of information: expression-level differences, over-representation of sequence motifs in promoter regions, and gene ontology annotations. A weight was attached to each analysis based on how well it identified BCL6-bound genes as defined by publicly available ChIP-chip data. By the organizers' criteria, our group, GenomeSingapore, performed best. However, our retrospective analysis indicates that this success was dominated by a gene expression analysis that was predicated on a regulatory model known to be favored by the organizers. We also noted that the 200-gene test set was enriched only in genes that are upregulated, while genes bound by BCL6 are enriched in both upregulated and downregulated genes. Together, these observations suggest possible model biases in the selection of the gold-standard gene set and imply that our success was attained in part by adhering to the same assumptions. We argue that model biases of this type are unavoidable in the inference of regulatory networks and, for that reason, we suggest that future community-wide experiments of this type should focus on the prediction of data, rather than models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}