Modeling of epigenome dynamics identifies transcription factors that mediate Polycomb targeting.
Modeling of epigenome dynamics identifies transcription factors that mediate Polycomb targeting.
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DOI：
10.1101/gr.142661.112
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发表时间：
2013-01
期刊：
影响因子：
7
通讯作者：
Schübeler D
中科院分区：
文献类型：
--
作者：
Arnold P;Schöler A;Pachkov M;Balwierz PJ;Jørgensen H;Stadler MB;van Nimwegen E;Schübeler D
尽管染色质的变化是细胞分化过程中转录重编程不可或缺的一部分，但目前尚不清楚染色质修饰如何针对特定位点。为了系统地识别在细胞命运决定过程中可以指导染色质变化的转录因子（TF），我们对染色质标记的全基因组动态与计算预测的 TF 结合位点的局部发生之间的关系进行了建模。通过将这种计算方法应用于小鼠干细胞神经元分化过程中 Polycomb 介导的 H3K27me3 标记的时间过程，我们确定了可能调节该染色质标记动态的几个基序。其中，REST 和 SNAIL 转录因子家族结合的位点预计会在神经祖细胞中短暂招募 H3K27me3。我们通过实验验证了这些预测，并表明 REST 的缺失确实会导致反式靶启动子处 H3K27me3 的丢失，特别是在神经元祖细胞状态下。此外，使用靶向转基因插入，我们发现含有 REST 或 SNAIL 结合位点的启动子片段足以以顺式方式招募 H3K27me3，而删除这些位点会导致 H3K27me3 丢失。这些发现表明 TF 结合位点的出现可以决定染色质动力学。通过 REST 和 SNAIL 基序对 Polycomb 活性的局部测定例证了这种基于 TF 的染色质调节。此外，我们的结果表明，可以使用我们易于使用的建模方法，通过表观基因组数据集的计算建模从头开始识别关键的转录因子。
Although changes in chromatin are integral to transcriptional reprogramming during cellular differentiation, it is currently unclear how chromatin modifications are targeted to specific loci. To systematically identify transcription factors (TFs) that can direct chromatin changes during cell fate decisions, we model the relationship between genome-wide dynamics of chromatin marks and the local occurrence of computationally predicted TF binding sites. By applying this computational approach to a time course of Polycomb-mediated H3K27me3 marks during neuronal differentiation of murine stem cells, we identify several motifs that likely regulate the dynamics of this chromatin mark. Among these, the sites bound by REST and by the SNAIL family of TFs are predicted to transiently recruit H3K27me3 in neuronal progenitors. We validate these predictions experimentally and show that absence of REST indeed causes loss of H3K27me3 at target promoters in trans, specifically at the neuronal progenitor state. Moreover, using targeted transgenic insertion, we show that promoter fragments containing REST or SNAIL binding sites are sufficient to recruit H3K27me3 in cis, while deletion of these sites results in loss of H3K27me3. These findings illustrate that the occurrence of TF binding sites can determine chromatin dynamics. Local determination of Polycomb activity by REST and SNAIL motifs exemplifies such TF based regulation of chromatin. Furthermore, our results show that key TFs can be identified ab initio through computational modeling of epigenome data sets using a modeling approach that we make readily accessible.
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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：
23.9
作者：
Brookes, Emily;de Santiago, Ines;Hebenstreit, Daniel;Morris, Kelly J.;Carroll, Tom;Xie, Sheila Q.;Stock, Julie K.;Heidemann, Martin;Eick, Dirk;Nozaki, Naohito;Kimura, Hiroshi;Ragoussis, Jiannis;Teichmann, Sarah A.;Pombo, Ana
通讯作者：
Pombo, Ana
影响因子：
5.3
作者：
Herranz, Nicolas;Pasini, Diego;Peiro, Sandra
通讯作者：
Peiro, Sandra
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
64.5
作者：
Czermin, B;Melfi, R;Pirrotta, V
通讯作者：
Pirrotta, V