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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.
摘要：
硬骨鱼斑马鱼和新生哺乳动物的心脏表现出通过预先存在的心肌细胞（CM）的去分化和增殖而再生的显着能力。尽管已经发现了许多刺激斑马鱼心脏再生的有丝分裂信号，抑制损伤诱导的CM更新的转录程序尚未完全了解。这里,我们报道了gridlock(grl;也称为hey2)中的突变，编码毛状相关的碱性螺旋-环-螺旋转录抑制因子，增强CM增殖并减少损伤后的纤维化。相比之下,心肌grl诱导减弱CM去分化和心脏损伤的再生反应。RNA测序分析揭示Smyd2赖氨酸甲基转移酶(KMT)是Grl抑制的关键转录靶标。损伤引发的Grl蛋白水平的降低诱导了伤口心肌的smyd2表达,增强CM增殖。我们证明Smyd2作为甲基转移酶起作用，并调节Stat3甲基化和磷酸化活性。抑制Smyd2的KMT活性可减少心脏伤口的磷酸化Stat3，抑制受损grl突变心脏中CM增殖的升高。我们的发现建立了一个损伤特异性转录抑制程序，在心脏再生过程中控制CM更新，提供一种潜在的策略，使局部区域的Grl抑制沉默可能会增强受损哺乳动物心脏的再生能力。
