Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming
Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming
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DOI：
10.1016/j.stem.2019.06.012
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发表时间：
2019-07-03
期刊：
影响因子：
23.9
通讯作者：
Srivastava, Deepak
中科院分区：
文献类型：
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作者：
Stone, Nicole R.;Gifford, Casey A.;Srivastava, Deepak
转录因子 (TF) 组合的异位表达可以驱动直接谱系转换，从而重新编程体细胞的身份。为了确定 Gata4、Mef2c 和 Tbx5 (GMT) 诱导心脏成纤维细胞向诱导心肌细胞转化的分子机制，我们在整个重编程过程中进行了全面的转录组学、DNA 占用和表观基因组研究。这些数据集的整合确定了参与心脏重编程的新 TF，并揭示了 GMT 的特定环境作用，包括 Mef2c 和 Tbx5 在以前无法访问的位点独立促进染色质重塑的能力。我们还发现了组合环境中每个 TF 结合特征的合作促进和细化的证据。采用新定义的调控元件的报告分析证实，单个 TF 的结合足以激活基因，这表明共结合事件不一定反映协同作用。这些结果揭示了转录因子组合直接谱系转换的基本机制。
Ectopic expression of combinations of transcription factors (TFs) can drive direct lineage conversion, thereby reprogramming a somatic cell's identity. To determine the molecular mechanisms by which Gata4, Mef2c, and Tbx5 (GMT) induce conversion from a cardiac fibroblast toward an induced cardiomyocyte, we performed comprehensive transcriptomic, DNA-occupancy, and epigenomic interrogation throughout the reprogramming process. Integration of these datasets identified new TFs involved in cardiac reprogramming and revealed context-specific roles for GMT, including the ability of Mef2c and Tbx5 to independently promote chromatin remodeling at previously inaccessible sites. We also find evidence for cooperative facilitation and refinement of each TF's binding profile in a combinatorial setting. A reporter assay employing newly defined regulatory elements confirmed that binding of a single TF can be sufficient for gene activation, suggesting that co-binding events do not necessarily reflect synergy. These results shed light on fundamental mechanisms by which combinations of TFs direct lineage conversion.