The histone reader PHF7 cooperates with the SWI/SNF complex at cardiac super enhancers to promote direct reprogramming.
The histone reader PHF7 cooperates with the SWI/SNF complex at cardiac super enhancers to promote direct reprogramming.
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DOI：
10.1038/s41556-021-00668-z
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发表时间：
2021-05
影响因子：
21.3
通讯作者：
Olson EN
中科院分区：
文献类型：
--
作者：
Garry GA;Bezprozvannaya S;Chen K;Zhou H;Hashimoto H;Morales MG;Liu N;Bassel-Duby R;Olson EN
直接心脏重编程成纤维细胞心肌细胞提出了一个有吸引力的治疗策略，以恢复损伤后的心脏功能。心脏重编程最初是通过转录因子Gata 4、Mef 2c和Tbx 5的过表达实现的;后来，发现Hand 2和Akt 1进一步增强了这一过程。然而，坚定的表观遗传障碍严重限制了这些鸡尾酒重新编程成人成纤维细胞的能力。我们进行了哺乳动物基因调节因子的筛选，以发现成人成纤维细胞中心脏重编程的新调节因子，并确定组蛋白阅读器PHF 7为最有效的激活因子。从机制上讲，PHF 7定位于成纤维细胞中的心脏超级增强子，并通过与SWI/SNF复合物的合作，增加了这些位点的染色质可及性和转录因子结合。此外，PHF 7招募心脏转录因子，以激活重编程中的正转录自动调节回路。重要的是，PHF 7在缺乏Gata 4的情况下实现了有效的重编程。在这里，我们强调了心脏表观遗传阅读器，如PHF 7，在利用染色质重塑和转录复合物克服直接心脏重编程的关键障碍的不足探索的必要性。
Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through overexpression of the transcription factors Gata4, Mef2c and Tbx5; later, Hand2 and Akt1 were found to further enhance this process. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogramme adult fibroblasts. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the histone reader PHF7 as the most potent activating factor. Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, it increases chromatin accessibility and transcription factor binding at these sites. Furthermore, PHF7 recruits cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. Importantly, PHF7 achieves efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic readers, such as PHF7, in harnessing chromatin remodelling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.
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DOI：
10.1073/pnas.1016959108
发表时间：
2011-04-05
影响因子：
11.1
作者：
He, Aibin;Kong, Sek Won;Pu, William T.
通讯作者：
Pu, William T.
影响因子：
7
作者：
Saint-André V;Federation AJ;Lin CY;Abraham BJ;Reddy J;Lee TI;Bradner JE;Young RA
通讯作者：
Young RA
影响因子：
64.8
作者：
Qian, Li;Huang, Yu;Srivastava, Deepak
通讯作者：
Srivastava, Deepak
影响因子：
1.2
作者：
Liu Z;Chen O;Zheng M;Wang L;Zhou Y;Yin C;Liu J;Qian L
通讯作者：
Qian L
影响因子：
64.5
作者：
Whyte WA;Orlando DA;Hnisz D;Abraham BJ;Lin CY;Kagey MH;Rahl PB;Lee TI;Young RA
通讯作者：
Young RA