MEF2C/p300-mediated epigenetic remodeling promotes the maturation of induced cardiomyocytes.
MEF2C/p300-mediated epigenetic remodeling promotes the maturation of induced cardiomyocytes.
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DOI：
10.1016/j.stemcr.2023.05.001
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发表时间：
2023-06-13
影响因子：
5.9
通讯作者：
Ieda, Masaki
中科院分区：
文献类型：
--
作者：
Kojima, Hidenori;Sadahiro, Taketaro;Muraoka, Naoto;Yamakawa, Hiroyuki;Hashimoto, Hisayuki;Ishii, Ryota;Gosho, Masahiko;Abe, Yuto;Yamada, Yu;Nakano, Koji;Honda, Seiichiro;Fujita, Ryo;Akiyama, Tatsuya;Sunagawa, Yoichi;Morimoto, Tatsuya;Tsukahara, Toshifumi;Hirai, Hiroyuki;Fukuda, Keiichi;Ieda, Masaki
心脏转录因子 (TF) 直接将成纤维细胞重编程为诱导心肌细胞 (iCM)，其中 MEF2C 与 GATA4 和 TBX5 (GT) 一起充当先锋因子。然而，功能性和成熟的 iCM 的生成效率低下，并且该过程背后的分子机制仍然很大程度上未知。在这里，我们发现，通过将强大的 MYOD 反式激活结构域与 GT 相融合，转录激活的 MEF2C 的过表达使跳动 iCM 的生成增加了 30 倍。带有 GT 的激活 MEF2C 生成的 iCM 在转录、结构和功能上比带有 GT 的天然 MEF2C 生成的 iCM 更加成熟。从机制上讲，激活的 MEF2C 将 p300 和多个心源性 TF 募集到心脏位点以诱导染色质重塑。相反，p300 抑制抑制心脏基因表达，抑制 iCM 成熟，并减少跳动 iCM 数量。具有相似转录活性的 MEF2C 剪接异构体不会促进功能性 iCM 的生成。因此，MEF2C/p300 介导的表观遗传重塑促进 iCM 成熟。转录激活的 MEF2C 通过 GT 促进心脏重编程 激活的 MEF2C 生成转录和结构上成熟的 iCM 激活的 MEF2C 招募 p300 和多个心脏 TF 进行染色质重塑 p300 敲低抑制心脏重编程和 iCM 成熟结果表明，转录激活的 MEF2C 的过度表达促进了心脏重编程。研究发现，激活的 MEF2C 可以产生诱导心肌细胞，这些细胞表现出更高的转录、结构和功能成熟度，T 管形成的存在证明了这一点。从机制上讲，激活的 MEF2C 将 p300 和多个心源性 TF 募集到心脏位点以诱导染色质重塑。
Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT). However, the generation of functional and mature iCMs is inefficient, and the molecular mechanisms underlying this process remain largely unknown. Here, we found that the overexpression of transcriptionally activated MEF2C via fusion of the powerful MYOD transactivation domain combined with GT increased the generation of beating iCMs by 30-fold. Activated MEF2C with GT generated iCMs that were transcriptionally, structurally, and functionally more mature than those generated by native MEF2C with GT. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling. In contrast, p300 inhibition suppressed cardiac gene expression, inhibited iCM maturation, and decreased the beating iCM numbers. Splicing isoforms of MEF2C with similar transcriptional activities did not promote functional iCM generation. Thus, MEF2C/p300-mediated epigenetic remodeling promotes iCM maturation. Transcriptionally activated MEF2C promotes cardiac reprogramming with GT Activated MEF2C generates transcriptionally and structurally mature iCMs Activated MEF2C recruits p300 and multiple cardiac TFs for chromatin remodeling p300 knockdown inhibits cardiac reprogramming and iCM maturation In this article, Ieda et al. showed that the overexpression of transcriptionally activated MEF2C promoted cardiac reprogramming. Activated MEF2C was found to generate induced cardiomyocytes that exhibit greater transcriptional, structural, and functional maturity, as evidenced by the presence of T-tubule formation. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling.
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