The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but a similar reference has lacked for epigenomic studies. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we describe the integrative analysis of 111 reference human epigenomes generated as part of the program, 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.
We present Omni-ATAC, an improved ATAC-seq protocol for chromatin
accessibility profiling that works across multiple applications with substantial
improvement of signal-to-background ratio and information content. The Omni-ATAC
protocol generates chromatin accessibility profiles from archival frozen tissue
samples and 50-μm sections, revealing the activities of
disease-associated DNA elements in distinct human brain structures. The
Omni-ATAC protocol enables the interrogation of personal regulomes in tissue
context and translational studies.
The spatial organization of chromatin is pivotal for regulating genome functions. We report an imaging method for tracing chromatin organization with kilobase- and nanometer-scale resolution, unveiling chromatin conformation across topologically associating domains (TADs) in thousands of individual cells. Our imaging data revealed TAD-like structures with globular conformation and sharp domain boundaries in single cells. The boundaries varied from cell to cell, occurring with non-zero probabilities at all genomic positions, but preferentially at CCCTC-binding factor (CTCF)- and cohesin-binding sites. Notably, cohesin depletion, which abolished TADs at the population-average level, did not diminish domain structures in single cells, but eliminated preferential TAD-like boundary positions. Moreover, we observed wide-spread, cooperative, multi-way chromatin interactions, which remained after cohesin depletion. These results provide critical insight into the mechanisms underlying chromatin domain and hub formation.
We present Omni-ATAC, an improved ATAC-seq protocol for chromatin accessibility profiling that works across multiple applications with substantial improvement of signal-tobackground ratio and information content. The Omni-ATAC protocol enables chromatin accessibility profiling from archival frozen tissue samples and 50 µm sections, revealing the activities of disease-associated DNA elements in distinct human brain structures. The Omni-ATAC protocol enables the interrogation of personal regulomes in tissue context and translational studies.
We analyzed 3,872 common genetic variants across the
ESR1 locus (encoding estrogen receptor α) in
118,816 subjects from three international consortia. We found evidence for at
least five independent causal variants, each associated with different phenotype
sets, including estrogen receptor (ER+ or
ER−) and human ERBB2 (HER2+ or
HER2−) tumor subtypes, mammographic density and tumor
grade. The best candidate causal variants for ER− tumors lie
in four separate enhancer elements, and their risk alleles reduce expression of
ESR1, RMND1 and CCDC170,
whereas the risk alleles of the strongest candidates for the remaining
independent causal variant disrupt a silencer element and putatively increase
ESR1 and RMND1 expression.
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