Sequence and chromatin determinants of cell-type-specific transcription factor binding.
Sequence and chromatin determinants of cell-type-specific transcription factor binding.
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DOI：
10.1101/gr.127712.111
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发表时间：
2012-09
期刊：
影响因子：
7
通讯作者：
Leslie C
中科院分区：
文献类型：
--
作者：
Arvey A;Agius P;Noble WS;Leslie C
不同细胞类型中的基因调控程序在很大程度上通过转录因子（TF）的细胞类型特异性结合来维持。TF结合的决定因素包括直接DNA序列偏好、辅因子的DNA序列偏好和局部细胞依赖性染色质背景。为了探索DNA序列信号，组蛋白修饰和DNA酶可及性对细胞类型特异性结合的贡献，我们分析了ENCODE联盟进行的286个ChIP-seq实验。该分析包括对67种转录调节因子的实验，其中15种在GM 12878（类淋巴母细胞）和K562（红白血病）人类造血细胞系中进行了分析。为了对TF结合区域进行建模，我们训练了支持向量机（SVM），该支持向量机使用灵活的k-mer模式来捕获DNA序列信号，比传统的基序方法更准确。此外，我们训练SVM空间染色质签名来模拟局部组蛋白修饰和DNA酶可及性，获得比简单方法更准确的TF占用预测。与以前的研究一致，我们发现DNA酶的可及性可以解释许多因素的细胞系特异性结合。然而，我们也发现，10个因素与突出的细胞类型特异性结合模式，四个显示不同的细胞类型特异性DNA序列的偏好，根据我们的模型。此外，对于两个因素，我们确定了细胞特异性结合位点，可在两种细胞类型，但仅在一个绑定。对于这些位点，细胞类型特异性序列模型，而不是DNA酶的可及性，能够更好地解释差异结合。我们的研究结果表明，使用一个单一的基序为每个TF和过滤染色质可访问的位点并不总是足以准确地考虑细胞类型特异性结合配置文件。
Gene regulatory programs in distinct cell types are maintained in large part through the cell-type–specific binding of transcription factors (TFs). The determinants of TF binding include direct DNA sequence preferences, DNA sequence preferences of cofactors, and the local cell-dependent chromatin context. To explore the contribution of DNA sequence signal, histone modifications, and DNase accessibility to cell-type–specific binding, we analyzed 286 ChIP-seq experiments performed by the ENCODE Consortium. This analysis included experiments for 67 transcriptional regulators, 15 of which were profiled in both the GM12878 (lymphoblastoid) and K562 (erythroleukemic) human hematopoietic cell lines. To model TF-bound regions, we trained support vector machines (SVMs) that use flexible k-mer patterns to capture DNA sequence signals more accurately than traditional motif approaches. In addition, we trained SVM spatial chromatin signatures to model local histone modifications and DNase accessibility, obtaining significantly more accurate TF occupancy predictions than simpler approaches. Consistent with previous studies, we find that DNase accessibility can explain cell-line–specific binding for many factors. However, we also find that of the 10 factors with prominent cell-type–specific binding patterns, four display distinct cell-type–specific DNA sequence preferences according to our models. Moreover, for two factors we identify cell-specific binding sites that are accessible in both cell types but bound only in one. For these sites, cell-type–specific sequence models, rather than DNase accessibility, are better able to explain differential binding. Our results suggest that using a single motif for each TF and filtering for chromatin accessible loci is not always sufficient to accurately account for cell-type–specific binding profiles.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
9.8
作者：
ENCODE Project Consortium
通讯作者：
ENCODE Project Consortium
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.5
作者：
Mullen AC;Orlando DA;Newman JJ;Lovén J;Kumar RM;Bilodeau S;Reddy J;Guenther MG;DeKoter RP;Young RA
通讯作者：
Young RA
影响因子：
4.3
作者：
Agius, Phaedra;Arvey, Aaron;Leslie, Christina
通讯作者：
Leslie, Christina