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.

In mammals and other eukaryotes most of the genome is transcribed in a developmentally regulated manner to produce large numbers of long non-coding RNAs (ncRNAs). Here we review the rapidly advancing field of long ncRNAs, describing their conservation, their organization in the genome and their roles in gene regulation. We also consider the medical implications, and the emerging recognition that any transcript, regardless of coding potential, can have an intrinsic function as an RNA.

Genomes of complex organisms encode an abundance and diversity of long noncoding RNAs (lncRNAs) that are expressed throughout the cell and fulfill a wide variety of regulatory roles at almost every stage of gene expression. These roles, which encompass sensory, guiding, scaffolding and allosteric capacities, derive from folded modular domains in lncRNAs. In this diverse functional repertoire, we focus on the well-characterized ability for lncRNAs to function as epigenetic modulators. Many lncRNAs bind to chromatin-modifying proteins and recruit their catalytic activity to specific sites in the genome, thereby modulating chromatin states and impacting gene expression. Considering this regulatory potential in combination with the abundance of lncRNAs suggests that lncRNAs may be part of a broad epigenetic regulatory network.

A major proportion of the mammalian transcriptome comprises long RNAs that have little or no protein-coding capacity (ncRNAs). Only a handful of such transcripts have been examined in detail, and it is unknown whether this class of transcript is generally functional or merely artifact. Using in situ hybridization data from the Allen Brain Atlas, we identified 849 ncRNAs (of 1,328 examined) that are expressed in the adult mouse brain and found that the majority were associated with specific neuroanatomical regions, cell types, or subcellular compartments. Examination of their genomic context revealed that the ncRNAs were expressed from diverse places including intergenic, intronic, and imprinted loci and that many overlap with, or are transcribed antisense to, proteincoding genes of neurological importance. Comparisons between the expression profiles of ncRNAs and their associated proteincoding genes revealed complex relationships that, in combination with the specific expression profiles exhibited at both regional and subcellular levels, are inconsistent with the notion that they are transcriptional noise or artifacts of chromatin remodeling. Our results show that the majority of ncRNAs are expressed in the brain and provide strong evidence that the majority of processed transcripts with no protein-coding capacity function intrinsically as RNAs.genomics ͉ neuroscience ͉ transcriptomics ͉ imprinting ͉ subcellular A lthough only 1.2% of the mammalian genome encodes proteins, it is now evident that most of the genome is transcribed to yield complex patterns of interlaced and overlapping transcripts that include tens of thousands of long (Ͼ200 nt) noncoding RNAs (ncRNAs) (1, 2). Although a small number of long ncRNAs have been functionally characterized (3), it remains a matter of debate whether the majority are biologically meaningful or merely transcriptional ''noise'' (4-7). The few long ncRNAs that have been characterized to date exhibit a diverse range of functions (3,8) and expression in specific cell types and/or localization to specific subcellular compartments (9-12). The determination of whether many more long ncRNAs are functional may considerably impact our understanding of various fundamental biological processes and significantly influence the approaches used to investigate them.If this class of long ncRNAs is indeed functional, one would expect that they would, in the main, show developmentally regulated and cell-specific expression patterns. The Allen Brain Atlas (ABA) is a large-scale study of the adult mouse brain that comprehensively catalogues and maps the patterns of gene expression that underlie brain development and function on a genome-wide scale (13). The ABA used high-throughput RNA in situ hybridization (ISH) to visualize the expression of over 20,000 mainly protein-coding transcripts from the mouse transcriptome at cellular resolution. We discovered that the ABA (13) also contained ISH data for many long ncRNAs. Our analysis of these data provides a landscape perspective of ncRNA expressi...