Abstract
BackgroundStretch enhancers (SEs) are large chromatin-defined regulatory elements that are at least 3,000 base pairs (bps) long, in contrast to the median enhancer length of 800 bps. SEs tend to be cell-type specific, regulate cell-type specific gene expression, and are enriched in disease-associated genetic variants in disease-relevant cell types. Transcription factors (TFs) can bind to enhancers to modulate enhancer activity, and their sequence specificity can be represented by motifs. We hypothesize motifs can provide a biological context for how genetic variants contribute to disease.ResultsWe integrated chromatin state, gene expression, and chromatin accessibility [measured as DNase I Hypersensitive Sites (DHSs)] maps across nine different cell types. Motif enrichment analyses of chromatin-defined enhancer sequences identify several known cell-type specific “master” factors. Furthermore, de novo motif discovery not only recovers many of these motifs, but also identifies novel non-canonical motifs, providing additional insight into TF binding preferences. Across the length of SEs, motifs are most enriched in DHSs, though relative enrichment is also observed outside of DHSs. Interestingly, we show that single nucleotide polymorphisms associated with diseases or quantitative traits significantly overlap motif occurrences located in SEs, but outside of DHSs.ConclusionsThese results reinforce the role of SEs in influencing risk for diseases and suggest an expanded regulatory functional role for motifs that occur outside highly accessible chromatin. Furthermore, the motif signatures generated here expand our understanding of the binding preference of well-characterized TFs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0015-7) contains supplementary material, which is available to authorized users.
Highlights
Stretch enhancers (SEs) are large chromatin-defined regulatory elements that are at least 3,000 base pairs long, in contrast to the median enhancer length of 800 bps
In our previous paper [3], we showed that enrichment for genome-wide association study (GWAS) variants increases with the length of enhancers, but we did not try to define the precise relationship of GWAS variants to motifs located within the enhancers—that is the goal of this paper
Systematic chromatin state, DNase hypersensitivity, and gene expression profiling across nine diverse cell types In our previous study, we used the ChromHMM algorithm to systematically integrate ChIP-seq histone modification and CTCF datasets and uniformly profile chromatin states across ten diverse cell types. These ChromHMM segmentations are used to profile stretch enhancer (SE), which are defined as regions of at least 3,000 bps containing contiguous segments marked as enhancer states
Summary
Stretch enhancers (SEs) are large chromatin-defined regulatory elements that are at least 3,000 base pairs (bps) long, in contrast to the median enhancer length of 800 bps. SEs tend to be cell-type specific, regulate celltype specific gene expression, and are enriched in disease-associated genetic variants in disease-relevant cell types. Chromatin immunoprecipitation combined with highthroughput sequencing (ChIP-seq) can identify the genome-wide locations of target proteins, including transcription factors (TFs), RNA Polymerase II, and covalently modified histones [1]. SEs are generally cell type specific, associated with increased cell-specific gene expression, and tend to harbor disease-relevant genetic variants derived from genome-wide association studies (GWASs). Like SEs, super-enhancers drive celltype-specific gene expression; super-enhancers have been defined by the disproportionate abundance of Mediator or histone 3 lysine 27 acetylation (H3K27ac)
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