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首页> 外文期刊>Epigenetics & Chromatin >Motif signatures in stretch enhancers are enriched for disease-associated genetic variants
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Motif signatures in stretch enhancers are enriched for disease-associated genetic variants

机译：拉伸增强子的基序特征丰富了与疾病相关的遗传变异

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Background 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 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. Results We 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. Conclusions These 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.
机译：背景拉伸增强子（SEs）是大型的染色质定义调控元件，其长度至少为3,000个碱基对（bps），而增强子的中位长度为800 bps。 SEs倾向于是细胞类型特异性的，调节细胞类型特异性基因的表达，并且在疾病相关细胞类型中富含与疾病相关的遗传变异。转录因子（TFs）可以与增强子结合以调节增强子的活性，其序列特异性可以由基序表示。我们假设基序可以为遗传变异如何导致疾病提供生物学背景。结果我们整合了9种不同细胞类型的染色质状态，基因表达和染色质可及性（以DNase I超敏位点（DHS）衡量）。染色质定义的增强子序列的母题富集分析确定了几种已知的细胞类型特异性“主”因子。此外，从头发现基序不仅可以恢复许多这些基序，而且还可以识别新颖的非经典基序，从而可以进一步了解TF结合偏好。在SE的整个长度上，基元在DHS中最富集，尽管在DHS之外也观察到相对富集。有趣的是，我们表明与疾病或数量性状相关的单核苷酸多态性与位于SEs中但不在DHSs中的基序出现显着重叠。结论这些结果加强了SEs在影响疾病风险中的作用，并暗示了在高度可及的染色质之外出现的基序具有更大的调节功能。此外，此处生成的基序签名扩展了我们对充分表征的TF的结合偏好的理解。

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