Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits

Case Western Reserve University
Genome Research (Impact Factor: 14.63). 11/2013; 24(1). DOI: 10.1101/gr.164079.113
Source: PubMed


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.

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    • "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. "
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    • "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 (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, ( "
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    • "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. "
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