title: Human Enhancers Are Fragile and Prone to Deactivating Mutations.
abstract: To explore the underlying mechanisms whereby noncoding variants affect transcriptional regulation, we identified nucleotides capable of disrupting binding of transcription factors and deactivating enhancers if mutated (dubbed candidate killer mutations or KMs) in HepG2 enhancers. On average, approximately 11% of enhancer positions are prone to KMs. A comparable number of enhancer positions are capable of creating de novo binding sites via a single-nucleotide mutation (dubbed candidate restoration mutations or RSs). Both KM and RS positions are evolutionarily conserved and tend to form clusters within an enhancer. We observed that KMs have the most deleterious effect on enhancer activity. In contrast, RSs have a smaller effect in increasing enhancer activity. Additionally, the KMs are strongly associated with liver-related Genome Wide Association Study traits compared with other HepG2 enhancer regions. By applying our framework to lymphoblastoid cell lines, we found that KMs underlie differential binding of transcription factors and differential local chromatin accessibility. The gene expression quantitative trait loci associated with the tissue-specific genes are strongly enriched in KM positions. In summary, we conclude that the KMs have the greatest impact on the level of gene expression and are likely to be the causal variants of tissue-specific gene expression and disease predisposition.
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD.
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD ovcharen@nih.gov.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ovcharenko
mesh_terms: D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D056945:Hep G2 Cells; D006801:Humans; D009154:Mutation; D009928:Organ Specificity / Q000235:genetics; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: causal mutations; enhancers; gene regulation; transcription factor binding sites