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.

Epigenetic Brainscape: Epigenetic modifications and their potential changes during development are of high interest, but few studies have characterized such differences.Listeret al.(1237905, published online 4 July; see the Perspective byGabel and Greenberg) report whole-genome base-resolution analysis of DNA cytosine modifications and transcriptome analysis in the frontal cortex of human and mouse brains at multiple developmental stages. The high-resolution mapping of DNA cytosine methylation (5mC) and one of its oxidation derivatives (5hmC) at key developmental stages provides a comprehensive resource covering the temporal dynamics of these epigenetic modifications in neurons compared to glia. The data suggest that methylation marks are dynamic during brain development in both humans and mice.

Regulation of gene expression by DNA methylation is crucial for defining cellular identities and coordinating organism-wide developmental programs in many organisms. In plants, modulation of DNA methylation in response to environmental conditions represents a potentially robust mechanism to regulate gene expression networks; however, examples of dynamic DNA methylation are largely limited to gene imprinting. Here we report an unexpected role for DNA methylation in regulation of the Arabidopsis thaliana immune system. Profiling the DNA methylomes of plants exposed to bacterial pathogen, avirulent bacteria, or salicylic acid (SA) hormone revealed numerous stress-induced differentially methylated regions, many of which were intimately associated with differentially expressed genes. In response to SA, transposon-associated differentially methylated regions, which were accompanied by up-regulation of 21-nt siRNAs, were often coupled to transcriptional changes of the transposon and/or the proximal gene. Thus, dynamic DNA methylation changes within repetitive sequences or transposons can regulate neighboring genes in response to SA stress.