Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk.
Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk.
复制标题
合并的芯片seq连接转录因子与复杂疾病风险结合的变化。
DOI：
10.1016/j.cell.2016.03.041
复制
发表时间：
2016-04-21
期刊：
影响因子：
64.5
通讯作者：
Fraser HB
中科院分区：
文献类型：
--
作者：
Tehranchi AK;Myrthil M;Martin T;Hie BL;Golan D;Fraser HB
转录因子 (TF) 结合位点等顺式调控元件可以在全基因组范围内进行鉴定，但查明影响 TF 结合的遗传变异仍然更具挑战性。在这里，我们介绍了一种基于池的方法来绘制分子水平性状的数量性状基因座（QTL）。将其应用于五个 TF 和一个组蛋白修饰，我们绘制了数千个顺式作用 QTL，与标准 QTL 绘制相比，成本降低了 25 倍以上。我们发现单个基因变异经常影响多个 TF 的结合，并且 CTCF 可以将所有 5 个 TF 招募到其结合位点。这些 QTL 通常影响局部染色质和转录，但也可以影响远程染色体接触，证明自然遗传变异在染色体结构中的作用。数千个这样的 QTL 已涉及全基因组关联研究，为许多疾病风险位点提供了候选分子机制，并表明 TF 结合变异可能是人类表型变异的很大一部分的基础。
Cis -regulatory elements such as transcription factor (TF) binding sites can be identified genome-wide, but it remains far more challenging to pinpoint genetic variants affecting TF binding. Here we introduce a pooling-based approach to mapping quantitative trait loci (QTLs) for molecular-level traits. Applying this to five TFs and a histone modification, we mapped thousands of cis-acting QTLs, with over 25-fold lower cost compared to standard QTL mapping. We found that single genetic variants frequently affect binding of multiple TFs, and that CTCF can recruit all five TFs to its binding sites. These QTLs often affect local chromatin and transcription, but can also influence long-range chromosomal contacts, demonstrating a role for natural genetic variation in chromosomal architecture. Thousands of these QTLs have been implicated in genome-wide association studies, providing candidate molecular mechanisms for many disease risk loci, and suggesting that TF binding variation may underlie a large fraction of human phenotypic variation.