The Gridlock transcriptional repressor impedes vertebrate heart regeneration by restricting expression of lysine methyltransferase.
The Gridlock transcriptional repressor impedes vertebrate heart regeneration by restricting expression of lysine methyltransferase.
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Gridlock转录抑制因子通过限制赖氨酸甲基转移酶的表达来阻碍脊椎动物心脏再生
DOI：
10.1242/dev.190678
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发表时间：
2020-09-28
期刊：
影响因子：
--
通讯作者：
Zhong TP
中科院分区：
文献类型：
--
作者：
She P;Zhang H;Peng X;Sun J;Gao B;Zhou Y;Zhu X;Hu X;Lai KS;Wong J;Zhou B;Wang L;Zhong TP
摘要硬骨鱼、斑马鱼和新生哺乳动物的心脏通过去分化和增殖心肌细胞而具有显著的再生能力。尽管已经确定了许多刺激斑马鱼心脏再生的有丝分裂信号，但抑制损伤诱导的CM更新的转录程序还不完全清楚。在这里，我们报告了gridlock（grl;也称为hey 2）中的突变，编码Hairy相关的基本螺旋-环-螺旋转录抑制因子，增强CM增殖并减少损伤后的纤维化。与此相反，心肌grl诱导钝化CM去分化和心脏损伤的再生反应。RNA测序分析揭示Smyd 2赖氨酸甲基转移酶（KMT）作为Grl抑制的关键转录靶点。损伤引起的Grl蛋白水平的降低诱导了创伤心肌的Smad 2表达，增强了CM增殖。我们发现Smyd 2作为甲基转移酶发挥作用，并调节Stat 3甲基化和磷酸化活性。抑制Smyd 2的KMT活性减少了心脏伤口处的磷酸化Stat 3，抑制了受损grl突变心脏中升高的CM增殖。我们的研究结果建立了一个损伤特异性转录抑制程序，在心脏再生过程中管理CM更新，提供了一个潜在的策略，使沉默Grl抑制在局部区域可能赋予再生能力受伤的哺乳动物心脏。突出显示的文章：Grl-Smyd 2网络的新机制支配脊椎动物CM更新和心脏再生，这可能与开发人类再生干预策略有关。
ABSTRACT Teleost zebrafish and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). Although many mitogenic signals that stimulate zebrafish heart regeneration have been identified, transcriptional programs that restrain injury-induced CM renewal are incompletely understood. Here, we report that mutations in gridlock (grl; also known as hey2), encoding a Hairy-related basic helix-loop-helix transcriptional repressor, enhance CM proliferation and reduce fibrosis following damage. In contrast, myocardial grl induction blunts CM dedifferentiation and regenerative responses to heart injury. RNA sequencing analyses uncover Smyd2 lysine methyltransferase (KMT) as a key transcriptional target repressed by Grl. Reduction in Grl protein levels triggered by injury induces smyd2 expression at the wound myocardium, enhancing CM proliferation. We show that Smyd2 functions as a methyltransferase and modulates the Stat3 methylation and phosphorylation activity. Inhibition of the KMT activity of Smyd2 reduces phosphorylated Stat3 at cardiac wounds, suppressing the elevated CM proliferation in injured grl mutant hearts. Our findings establish an injury-specific transcriptional repression program in governing CM renewal during heart regeneration, providing a potential strategy whereby silencing Grl repression at local regions might empower regeneration capacity to the injured mammalian heart. Highlighted Article: Novel mechanisms of the Grl-Smyd2 network govern vertebrate CM renewal and heart regeneration, which might be relevant in developing strategies for regeneration interventions in humans.
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影响因子：
16.6
作者：
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通讯作者：
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