Down-regulation of Beclin1 promotes direct cardiac reprogramming.
Down-regulation of Beclin1 promotes direct cardiac reprogramming.
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DOI：
10.1126/scitranslmed.aay7856
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发表时间：
2020-10-21
影响因子：
17.1
通讯作者：
Qian L
中科院分区：
文献类型：
--
作者：
Wang L;Ma H;Huang P;Xie Y;Near D;Wang H;Xu J;Yang Y;Xu Y;Garbutt T;Zhou Y;Liu Z;Yin C;Bressan M;Taylor JM;Liu J;Qian L
通过强制表达转录因子，直接将成纤维细胞重新编程为不同的细胞命运，为探索控制细胞命运身份的基本分子事件提供了一个平台。诱导心肌细胞(ICMs)的发现和研究不仅为心脏疾病的治疗提供了替代策略，而且为CM命运决定的基础生物学提供了线索。ICM领域主要关注早期转录组和表观组重构型，而对于重编程ICM如何重塑、擦除和退出最初的成纤维细胞谱系以获得最终的细胞身份知之甚少。在这里，我们证明了自噬相关的5(ATG5)依赖的自噬是一种进化上保守的自我消化过程，是ICM重新编程所必需的。出乎意料的是，自噬因子Beclin1(Becn1)被发现以一种非自噬的方式抑制ICM的诱导。去除Becn1基因可提高鼠和人成纤维细胞的ICM诱导率。在小鼠遗传模型中，Becn1单倍体不足进一步增强了重编程因子介导的心功能恢复和心肌梗死后疤痕大小的减少。从机制上讲，BECN1的缺失上调了Lef1的表达，下调了Wnt抑制剂的表达，导致了典型的Wnt/β-catenin信号通路的激活。此外，Becn1还与其他经典的III类磷脂酰肌醇3-激酶(PI3K III)复合体相互作用，在心脏重编程过程中，其被击倒的现象导致Becn1耗竭。总而言之，我们的研究揭示了依赖ATG5的自噬的诱导作用以及先前未知的Becn1在ICM重编程中的自噬非依赖性抑制功能。
Direct reprogramming of fibroblasts to alternative cell fates by forced expression of transcription factors offers a platform to explore fundamental molecular events governing cell fate identity. The discovery and study of induced cardiomyocytes (iCMs) not only provides alternative therapeutic strategies for heart disease but also sheds lights on basic biology underlying CM fate determination. The iCM field has primarily focused on early transcriptome and epigenome repatterning, whereas little is known about how reprogramming iCMs remodel, erase, and exit the initial fibroblast lineage to acquire final cell identity. Here, we show that autophagy-related 5 (Atg5)–dependent autophagy, an evolutionarily conserved self-digestion process, was induced and required for iCM reprogramming. Unexpectedly, the autophagic factor Beclin1 (Becn1) was found to suppress iCM induction in an autophagy-independent manner. Depletion of Becn1 resulted in improved iCM induction from both murine and human fibroblasts. In a mouse genetic model, Becn1 haploinsufficiency further enhanced reprogramming factor–mediated heart function recovery and scar size reduction after myocardial infarction. Mechanistically, loss of Becn1 up-regulated Lef1 and down-regulated Wnt inhibitors, leading to activation of the canonical Wnt/β-catenin signaling pathway. In addition, Becn1 physically interacts with other classical class III phosphatidylinositol 3-kinase (PI3K III) complex components, the knockdown of which phenocopied Becn1 depletion in cardiac reprogramming. Collectively, our study revealed an inductive role of Atg5-dependent autophagy as well as a previously unrecognized autophagy-independent inhibitory function of Becn1 in iCM reprogramming.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
21.3
作者：
通讯作者：
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Beclin1 通过调节 USP10 和 USP13 的去泛素化活性来控制 p53 的水平。
影响因子：
64.5
作者：
Liu J;Xia H;Kim M;Xu L;Li Y;Zhang L;Cai Y;Norberg HV;Zhang T;Furuya T;Jin M;Zhu Z;Wang H;Yu J;Li Y;Hao Y;Choi A;Ke H;Ma D;Yuan J
通讯作者：
Yuan J
影响因子：
7.2
作者：
Cruciat, Cristina-Maria;Niehrs, Christof
通讯作者：
Niehrs, Christof
影响因子：
23.9
作者：
Karow, Marisa;Sanchez, Rodrigo;Berninger, Benedikt
通讯作者：
Berninger, Benedikt