Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts.
Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts.
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DOI：
10.1038/celldisc.2016.36
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发表时间：
2016
期刊：
影响因子：
33.5
通讯作者：
Wang, Zhong
中科院分区：
文献类型：
--
作者：
Liu, Liu;Lei, Ienglam;Karatas, Hacer;Li, Yangbing;Wang, Li;Gnatovskiy, Leonid;Dou, Yali;Wang, Shaomeng;Qian, Li;Wang, Zhong
直接从成纤维细胞生成诱导心肌细胞（iCMs）为心脏病建模和心脏再生提供了巨大的机会。iCM生成的一个主要挑战是低转换率。为了解决这个问题，我们试图通过去除抑制障碍来识别可以增强心脏命运重编程能力的小分子。以小鼠胚胎成纤维细胞为起始细胞源，我们首先筛选了47个心脏发育相关的表观遗传和转录因子，并发现了H3K4甲基转移酶Mll1和相关因子Men1在抑制iCM重编程中的意外作用。然后，我们应用Mll1途径抑制剂的小分子（MM408和MI503），观察到将胚胎成纤维细胞和心脏成纤维细胞转化为功能性心肌细胞样细胞的效率提高。我们进一步观察到这些抑制剂直接抑制参与脂肪细胞分化的Mll1靶基因Ebf1的表达。因此，在iCM诱导过程中，Mll1抑制显著减少了脂肪细胞的形成。因此，Mll1抑制剂可能通过抑制替代谱系基因表达来提高iCM效率。我们的研究表明，靶向Mll1依赖性H3K4甲基转移酶活性在心脏重编程过程中提供了特异性。这些发现揭示了成纤维细胞心脏转化的分子机制，并为临床应用改善iCM重编程提供了新的靶点和小分子。
Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers a great opportunity for cardiac disease modeling and cardiac regeneration. A major challenge of iCM generation is the low conversion rate. To address this issue, we attempted to identify small molecules that could potentiate the reprogramming ability towards cardiac fate by removing inhibitory roadblocks. Using mouse embryonic fibroblasts as the starting cell source, we first screened 47 cardiac development related epigenetic and transcription factors, and identified an unexpected role of H3K4 methyltransferase Mll1 and related factor Men1 in inhibiting iCM reprogramming. We then applied small molecules (MM408 and MI503) of Mll1 pathway inhibitors and observed an improved efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. We further observed that these inhibitors directly suppressed the expression of Mll1 target gene Ebf1 involved in adipocyte differentiation. Consequently, Mll1 inhibition significantly decreased the formation of adipocytes during iCM induction. Therefore, Mll1 inhibitors likely increased iCM efficiency by suppressing alternative lineage gene expression. Our studies show that targeting Mll1 dependent H3K4 methyltransferase activity provides specificity in the process of cardiac reprogramming. These findings shed new light on the molecular mechanisms underlying cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications.
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作者：
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通过对心脏转录因子的非肌细胞进行重编程通过重编程。
影响因子：
64.8
作者：
Song, Kunhua;Nam, Young-Jae;Luo, Xiang;Qi, Xiaoxia;Tan, Wei;Huang, Guo N.;Acharya, Asha;Smith, Christopher L.;Tallquist, Michelle D.;Neilson, Eric G.;Hill, Joseph A.;Bassel-Duby, Rhonda;Olson, Eric N.
通讯作者：
Olson, Eric N.