An atlas of active enhancers across human cell types and tissues

Abstract

SUMMARY Enhancers control the correct temporal and cell type-specific activation of gene expression in higher eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. We use the FANTOM5 panel of samples covering the majority of human tissues and cell types to produce an atlas of active, in vivo transcribed enhancers. We show that enhancers share properties with CpG-poor mRNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, identify disease-associated regulatory single nucleotide polymorphisms, and classify cell type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell type-specific enhancers and gene regulation.

The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

“…S3). Intriguingly, we also found that rs4759229 lies within a known enhancer element (chr12:56474601e56474862) based on FANTOM5 human active enhancer atlas (Andersson et al, 2014). Taken together, these data indicate that rs2292239, rs3741499, and rs4759229 might be functional SNPs with regulatory implications.…”

“…Some of these variations could be of functional significance particularly those that lie within the binding sites of known TFs. Generally, functional TF binding is enriched at sites that are enriched in active enhancers, regulatory elements harboring multiple TF binding sites, and at sites with predicted higher binding affinity (Andersson et al, 2014;Cusanovich et al, 2014). Our analysis points towards the functional significance of SNPs rs2292239, rs3741499 and rs4759229 based on the overlap with an active enhancer element, CLIP-Seq peaks and DNase I footprints coverage, and the existence of multiple TF binding sites.…”

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

“…We clustered TSS separated by less that 500 nt and selected the center and strand of strongest TSS/DPI as a representative for a given group of TSS cluster, which led to the selection of 21,251 centers with strand information (representing 14,685 out of 24,045 merged acetylation peaks). Second, we overlapped the remaining 9,360 acetyl peaks with bidirectionally transcribed enhancer annotated from FANTOM5 [71,72] and found 3,161 enhancer-overlapping 2,448 acetyl sites. We clustered enhancer separated by less that 500 nt and selected the strongest enhancer within each group, 2,815 in total.…”

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…epigenomics roadmap,97, 98 FANTOM99, 100, 101, 102). In the post‐GWAS era, there are very strong data linking genetic variation (single nucleotide polymorphism or snp) in a wide variety of immunological disease cohorts, but identification of individual causal target genes has been difficult, as it is now apparent that the majority of this genetic variation does not disrupt the coding region of genes, but is located in noncoding regions 103.…”

“…Localised patterns of chromatin modification, such as DNA methylation, histone modification and nucleosome remodelling, correlate with enhancer activity, transcription factor binding and initiation or repression of transcription 99, 109, 110. More recently, these approaches have enabled the identification of a rare subset of enhancers, termed super‐enhancers 103, 107.…”