Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers
Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers
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DOI：
10.1016/j.stem.2019.03.022
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发表时间：
2019-07-03
期刊：
影响因子：
23.9
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
--
作者：
Hashimoto, Hisayuki;Wang, Zhaoning;Olson, Eric N.
心源性转录因子（TFs） Mef2c、Gata4和Tbx5可以直接重编程成纤维细胞，诱导成心肌细胞（iCLMs），为心脏修复提供了潜在的细胞来源。虽然Hand2和Akt1增强了这些tf的活性，但它们的基因组靶点和重编程过程中的相互作用尚未得到很好的研究。我们对心脏重编程过程中的心源性TF结合和增强子谱进行了全基因组分析。我们发现这些tf协同激活Mef2c结合位点突出的增强子，并且Hand2和Akt1协同招募其他tf来增强元件。有趣的是，这些增强子的景观共同类似于胚胎心脏发生过程中增强子的激活模式。我们进一步构建了心脏重编程基因调控网络，发现了EGFR信号通路基因的抑制。自始至终，EGFR信号的化学抑制增强了重编程。因此，通过定义表观遗传景观，这些发现揭示了在心脏增强子和控制iCLM重编程的关键信号通路的广泛景观中协同转录激活。
The cardiogenic transcription factors (TFs) Mef2c, Gata4, and Tbx5 can directly reprogram fibroblasts to induced cardiac-like myocytes (iCLMs), presenting a potential source of cells for cardiac repair. While activity of these TFs is enhanced by Hand2 and Akt1, their genomic targets and interactions during reprogramming are not well studied. We performed genome-wide analyses of cardiogenic TF binding and enhancer profiling during cardiac reprogramming. We found that these TFs synergistically activate enhancers highlighted by Mef2c binding sites and that Hand2 and Akt1 coordinately recruit other TFs to enhancer elements. Intriguingly, these enhancer landscapes collectively resemble patterns of enhancer activation during embryonic cardiogenesis. We further constructed a cardiac reprogramming gene regulatory network and found repression of EGFR signaling pathway genes. Consistently, chemical inhibition of EGFR signaling augmented reprogramming. Thus, by defining epigenetic landscapes these findings reveal synergistic transcriptional activation across a broad landscape of cardiac enhancers and key signaling pathways that govern iCLM reprogramming.