DNA variants (SNPs) that predispose to common traits often localize within noncoding regulatory elements such as enhancers. Moreover, loci identified by genome-wide association studies (GWAS) often contain multiple SNPs in linkage disequilibrium (LD), any of which may be causal. Thus, determining the effect of these multiple variant SNPs on target transcript levels has been a major challenge. Here, we provide evidence that for six common autoimmune disorders (rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis), the GWAS-association arises from multiple polymorphisms in LD that map to clusters of enhancer elements active in the same cell type. This finding suggests a "multiple enhancer variant" hypothesis for common traits, where several variants in LD impact multiple enhancers and cooperatively affect gene expression. Using a novel method to delineate enhancer-gene interactions, we show that multiple enhancer variants within a given locus typically target the same gene. Using available data from HapMap and B lymphoblasts as a model system, we provide evidence at numerous loci that multiple enhancer variants cooperatively contribute to altered expression of their gene targets. The effects on target transcript levels tend to be modest and can be either gain- or loss-of-function. Additionally, the genes associated with multiple enhancer variants encode proteins that are often functionally related and enriched in common pathways. Overall, the multiple enhancer variant hypothesis offers a new paradigm by which noncoding variants can confer susceptibility to common traits.
"Even genes expressed broadly across different cell types can show dramatic differences in enhancer usage (Kieffer-Kwon et al., 2013). Recent evidence suggests that large genomic domains containing clusters of active enhancers, variously referred to as ''super enhancers,'' ''stretch enhancers,'' or ''multiple enhancer variants'' are particularly cell type specific, and they are proposed to mediate transcription of genes that are important for controlling cell identity (Corradin et al., 2014; Hnisz et al., 2013; Lové n et al., 2013; Parker et al., 2013; Whyte et al., 2013). These discoveries have largely been garnered from comparisons of regulatory landscapes of cell types derived from very different tissues and distinct stages of development. "
[Show abstract][Hide abstract] ABSTRACT: Naive mouse embryonic stem cells (mESCs) and primed epiblast stem cells (mEpiSCs) represent successive snapshots of pluripotency during embryogenesis. Using transcriptomic and epigenomic mapping we show that a small fraction of transcripts are differentially expressed between mESCs and mEpiSCs and that these genes show expected changes in chromatin at their promoters and enhancers. Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically. In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which we term seed enhancers. In mEpiSCs, the naive-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control. Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers. We propose that seed enhancers ensure proper enhancer utilization and transcriptional fidelity as mammalian cells transition from naive pluripotency to a somatic regulatory program.
"For all seven enhancers of the 32 kb RLS-associated region, interactions were analyzed based on predictions from " PreSTIGE " software using thirteen human cell lines, as available at http://genetics.case.edu/prestige/ (Corradin et al. 2014). Poll II ChIA-PET (Fullwood and Ruan 2009; Li et al. 2012) and Hi-C (Belton et al. 2012; Dixon et al. 2012) data from the human epigenomic browser of the Washington University School of Medicine, St.Louis, USA, (http://epigenomegateway.wustl.edu/info/) "
"Indeed, genome-wide and other studies have shown that single-nucleotide polymorphisms (SNPs), insertions, or deletions at disease-associated enhancers can alter the gene expression of respective target genes by positively or negatively affecting the recruitment of transcription factors and cofactors, thus changing the epigenetic enhancer landscape. Also, specific enhancer mutations have been correlated with various diseaselinked genes for X-linked deafness, Hirschsprung's disease, Crohn's disease, multiple sclerosis, systemic lupus, and others (Corradin et al., 2013; de Kok et al., 1996; Emison et al., 2005; Kasowski et al., 2013; Kilpinen et al., 2013; Maurano et al., 2012; McVicker et al., 2013; Noonan and McCallion, 2010). As (C) A looping mechanism mediated by factors such as cohesin and the Mediator complex can bring enhancers into close proximity to promoters. "
[Show abstract][Hide abstract] ABSTRACT: Why certain point mutations in a general transcription factor are associated with specific forms of cancer has been a major question in cancer biology. Enhancers are DNA regulatory elements that are key regulators of tissue-specific gene expression. Recent studies suggest that enhancer malfunction through point mutations in either regulatory elements or factors modulating enhancer-promoter communication could be the cause of tissue-specific cancer development. In this Perspective, we will discuss recent findings in the identification of cancer-related enhancer mutations and the role of Drosophila Trr and its human homologs, the MLL3 and MLL4/COMPASS-like complexes, as enhancer histone H3 lysine 4 (H3K4) monomethyltransferases functioning in enhancer-promoter communication. Recent genome-wide studies in the cataloging of somatic mutations in cancer have identified mutations in intergenic sequences encoding regulatory elements-and in MLL3 and MLL4 in both hematological malignancies and solid tumors. We propose that cancer-associated mutations in MLL3 and MLL4 exert their properties through the malfunction of Trr/MLL3/MLL4-dependent enhancers.
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