DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal.
DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal.
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DOI：
10.1038/s41467-022-35070-2
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发表时间：
2022-12-02
影响因子：
16.6
通讯作者：
Evans, Sylvia M.
中科院分区：
文献类型：
--
作者：
Cattaneo, Paola;Hayes, Michael G. B.;Baumgarten, Nina;Hecker, Dennis;Peruzzo, Sofia;Aslan, Galip S.;Kunderfranco, Paolo;Larcher, Veronica;Zhang, Lunfeng;Contu, Riccardo;Fonseca, Gregory;Spinozzi, Simone;Chen, Ju;Condorelli, Gianluigi;Dimmeler, Stefanie;Schulz, Marcel H.;Heinz, Sven;Guimaraes-Camboa, Nuno;Evans, Sylvia M.
特定组蛋白修饰调节不同基因网络的机制仍知之甚少。我们研究了 H3K79me2（一种由 DOT1L 催化的修饰，之前被认为是一般转录激活标记）如何在心脏发生过程中调节基因表达。 Dot1l 的胚胎心肌细胞消融表明，H3K79me2 并不充当一般的转录激活剂，而是在两个关键的心源性关口调节高度特异性的转录网络：胚胎心脏发生，其中对左心室特异性基因特别重要，以及出生后心肌细胞周期退出，Dot1L 突变体具有更多的单核心肌细胞和延长的心肌细胞周期活性。机制分析表明，H3K79me2 在两个不同的域（基因体和调控元件）中协同促进 DOT1L 激活的基因的表达。令人惊讶的是，特定调控元件中的 H3K79me2 也有助于沉默通常在心肌细胞中不表达的基因。这些结果揭示了 DOT1L 连续调节左心室规格和心肌细胞周期退出的机制。组蛋白修饰如何以及是否调节不同的基因网络仍不清楚。 Cattaneo 等人在此表明，DOT1L 催化的 H3K79me2 调节胎儿腔室特异性基因表达和新生儿心肌细胞周期退出以协调心脏发育。
Mechanisms by which specific histone modifications regulate distinct gene networks remain little understood. We investigated how H3K79me2, a modification catalyzed by DOT1L and previously considered a general transcriptional activation mark, regulates gene expression during cardiogenesis. Embryonic cardiomyocyte ablation of Dot1l revealed that H3K79me2 does not act as a general transcriptional activator, but rather regulates highly specific transcriptional networks at two critical cardiogenic junctures: embryonic cardiogenesis, where it was particularly important for left ventricle-specific genes, and postnatal cardiomyocyte cell cycle withdrawal, with Dot1L mutants having more mononuclear cardiomyocytes and prolonged cardiomyocyte cell cycle activity. Mechanistic analyses revealed that H3K79me2 in two distinct domains, gene bodies and regulatory elements, synergized to promote expression of genes activated by DOT1L. Surprisingly, H3K79me2 in specific regulatory elements also contributed to silencing genes usually not expressed in cardiomyocytes. These results reveal mechanisms by which DOT1L successively regulates left ventricle specification and cardiomyocyte cell cycle withdrawal. How and whether histone modifications regulate distinct gene networks remains insufficiently understood. Here Cattaneo et al show that DOT1L catalyzed H3K79me2 regulates fetal chamber-specific gene expression and neonatal cardiomyocyte cell cycle withdrawal to coordinate heart development.
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