Showing papers by "Xin Zhou published in 2015"
Massachusetts Institute of Technology1, Broad Institute2, University of California, Los Angeles3, University of British Columbia4, Baylor College of Medicine5, Howard Hughes Medical Institute6, University of Washington7, Ludwig Institute for Cancer Research8, University of California, San Francisco9, University of Connecticut10, University of Zagreb11, University of Texas at Austin12, Washington University in St. Louis13, University of Queensland14, Harvard University15, Cold Spring Harbor Laboratory16, University of Southern California17, University of California, Santa Cruz18, Simon Fraser University19, Morgridge Institute for Research20, University of Texas at Dallas21, National Institutes of Health22
TL;DR: It is shown that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
5,037 citations
TL;DR: Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer, and family history did not predict the presence of an underlying predisposition syndrome in most patients.
Abstract: BackgroundThe prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. MethodsIn 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data...
886 citations
TL;DR: It is concluded that intermediate DNA methylation is a conserved signature of gene regulation and exon usage, highlighting gene context-dependent functions.
Abstract: The role of intermediate methylation states in DNA is unclear. Here, to comprehensively identify regions of intermediate methylation and their quantitative relationship with gene activity, we apply integrative and comparative epigenomics to 25 human primary cell and tissue samples. We report 18,452 intermediate methylation regions located near 36% of genes and enriched at enhancers, exons and DNase I hypersensitivity sites. Intermediate methylation regions average 57% methylation, are predominantly allele-independent and are conserved across individuals and between mouse and human, suggesting a conserved function. These regions have an intermediate level of active chromatin marks and their associated genes have intermediate transcriptional activity. Exonic intermediate methylation correlates with exon inclusion at a level between that of fully methylated and unmethylated exons, highlighting gene context-dependent functions. We conclude that intermediate DNA methylation is a conserved signature of gene regulation and exon usage.
92 citations
TL;DR: The Roadmap Epigenome Browser is described, which is based on the WashU Epigenomes Browser and integrates data from both the NIH Road map Epigenomics Consortium and ENCODE in a visualization and bioinformatics tool that enables researchers to explore the tissue-specific regulatory roles of genetic variants in the context of disease.
Abstract: 1 Investigators interact with the browser to determine the tissue specificity of the epigenetic state encompassing genetic variants in physiologically or pathogenically relevant cell types from normal or diseased samples (Supplementary Note, Supplementary Tutorial 1 and Supplementary Figs. 3 and 4). We illustrate the epigenomic annotation of two noncoding SNPs, identified from genome-wide association studies of people with multiple sclerosis10, by clustering the histone H3K4me1 profile of SNP-harboring regions and RNA-seq signal of their closest genes across multiple primary tissues and cells (Fig. 1). Both SNPs lie within putative enhancer regions. Whereas rs307896 marks an enhancer common across cell types, rs756699 is located in an enhancer specific to immune cells and is potentially targeting TCF7, a T cell–specific gene 3.8 kb downstream (Fig. 1 and Supplementary Fig. 5). Thus, reference epigenomes provide important clues into the functional To the Editor: Advances in next-generation sequencing platforms have reshaped the landscape of functional genomic and epigenomic research as well as human genetics studies. Annotation of noncoding regions in the genome with genomic and epigenomic data has facilitated the generation of new, testable hypotheses regarding the functional consequences of genetic variants associated with human complex traits1,2. Large consortia, such as the US National Institutes of Health (NIH) Roadmap Epigenomics Consortium3 and ENCODE4, have generated tens of thousands of sequencing-based genomewide data sets, creating a useful resource for the scientific community5. The WashU Epigenome Browser6–8 continues to provide a platform for investigators to effectively engage with this resource in the context of analyzing their own data. Here, we describe the Roadmap Epigenome Browser (http:// epigenomegateway.wustl.edu/browser/ roadmap/), which is based on the WashU Epigenome Browser and integrates data from both the NIH Roadmap Epigenomics Consortium and ENCODE in a visualization and bioinformatics tool that enables researchers to explore the tissue-specific regulatory roles of genetic variants in the context of disease. The browser takes advantage of the over 10,000 epigenomic data sets it currently hosts, including 346 ‘complete epigenomes’, defined as tissues and cell types for which we have collected a complete set of DNA methylation, histone modification, open chromatin and other genomic data sets9. Data from both the NIH Roadmap Epigenomics and ENCODE resources are seamlessly integrated in the browser using a new Data Hub Cluster framework (Supplementary Note and Supplementary Figs. 1 and 2). Investigators can specify any number of single nucleotide polymorphism (SNP)-associated regions and any type of epigenomic data, for which the browser automatically creates virtual data hubs through a shared hierarchical metadata annotation, retrieves the data and performs real-time clustering analysis. Epigenomic annotation of genetic variants using the Roadmap Epigenome Browser
84 citations