Integrative analysis of 111 reference human epigenomes

Abstract

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.

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

“…First, we obtained additional annotation information. We obtained histone marks and DNase I hypersensitive sites data from the Roadmap Epigenomics Consortium14; we obtained eQTLs derived from brain regions from the UK Brain Expression Consortium10 and the GTEx Consortium9; and we obtained promoter capture HiC array express data in CD34 (a marker of immature hematopoietic cells) cells from GM12878 (reference: E‐MTAB‐2323) 35. We also considered two gene sets.…”

“…For brain tissue, we defined a union set of histone marks plus DNase I hypersensitive sites from the Roadmap Epigenomics Consortium14 using the same aggregation procedure as above. This processing resulted in one annotation per brain region (10 annotations).…”

“…Among specific immune cells, we assessed the histone marks described previously,31 and also the histone marks and DNase I hypersensitive site data from the Roadmap Epigenomics Consortium for immune and blood cells,14 and we took the union for each cell type as described above (three histone marks and DNase I hypersensitive site). This resulted in 20 annotations from Finucane et al31 and 14 annotations from Roadmap.…”

“…Efforts to obtain brain samples (the most obviously relevant tissue for neurodegenerative diseases) for eQTL analyses are ongoing 8, 9, 10, 11, 12, 13. There has been a recent proliferation in the availability of cell‐type and tissue‐specific annotations, including brain tissue, for example, through the Roadmap Epigenomics Project14 and the PsychEncode Project 11. Nevertheless, obtaining large numbers of post mortem human brains remains challenging, and current eQTL analyses are likely to be underpowered.…”

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

“…This has reinforced the notion that mammalian DNA methylation primarily functions as an epigenetic mark for cell‐type specification (Roadmap Epigenomics Consortium et al . 2015). Furthermore, DNA methylation changes are also considered to facilitate cellular adaptation to changing environments and have repeatedly been linked to human diseases and aging (Feinberg, 2007).…”