Integrative analysis of 111 reference human epigenomes

TLDR

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. The NIH Roadmap Epigenomics Consortium generated and analyzed 111 reference human epigenomes, profiling histone modifications, DNA accessibility, methylation, and RNA expression to address this gap. They profiled 111 primary cells and tissues for these marks, then constructed global maps of regulatory elements, defined coordinated regulatory modules, and inferred their likely activators and repressors. Disease‑ and trait‑associated variants are enriched in tissue‑specific epigenomic marks, highlighting relevant cell types and underscoring epigenomics’ central role in gene regulation, differentiation, and disease interpretation.

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.