Kindlin-2 suppresses transcription factor GATA4 through interaction with SUV39H1 to attenuate hypertrophy
Kindlin-2 suppresses transcription factor GATA4 through interaction with SUV39H1 to attenuate hypertrophy
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Kindlin-2 通过与 SUV39H1 相互作用抑制转录因子 GATA4 以减轻肥大
DOI：
10.1038/s41419-019-2121-0
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发表时间：
2019-11-26
影响因子：
9
通讯作者：
Zhang, Hongquan
中科院分区：
文献类型：
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作者：
Qi, Lihua;Chi, Xiaochun;Zhang, Hongquan
Kindlin-2在心脏结构和功能的调节中起重要作用。Kindlin-2的缺失导致心脏肥大和进行性心力衰竭，然而，参与该过程的确切机制仍不清楚。GATA 4是调节心脏发生的关键转录因子。我们发现Kindlin-2通过与其启动子结合抑制GATA 4的表达，并防止异丙肾上腺素（ISO）处理诱导的心肌细胞肥大。在机制上，Kindlin-2与组蛋白甲基转移酶SUV 39 H1相互作用，并将其募集到GATA 4启动子，导致组蛋白H3 K9二甲基化和三甲基化的占据。此外，为了证实Kindlin-2在体内的功能，我们产生了心脏Kindlin-2靶向缺失的小鼠。我们发现，6个月大的Kindlin-2 cKO小鼠已发展为肥厚型心肌病，并且ISO治疗可加速该病理过程。与野生型动物相比，Kindlin-2 cKO小鼠的心脏组织中GATA 4表达显著活化。总的来说，我们的数据显示Kindlin-2通过部分触发组蛋白H3 K9甲基化来抑制GATA 4表达，并保护心脏免受病理性肥大。
Kindlin-2 plays an important role in the regulation of cardiac structure and function. Depletion of Kindlin-2 contributes to cardiac hypertrophy and progressive heart failure, however, the precise mechanisms involved in this process remain unclear. GATA4 is a critical transcription factor in regulating cardiogenesis. We found that Kindlin-2 suppresses the expression of GATA4 through binding to its promoter and prevents cardiomyocytes from hypertrophy induced by isoproterenol (ISO) treatment. Mechanistically, Kindlin-2 interacts with histone methyltransferase SUV39H1 and recruits it to GATA4 promoter leading to the occupancy of histone H3K9 di- and tri-methylation. Furthermore, to confirm the function of Kindlin-2 in vivo, we generated mice with targeted deletion of cardiac Kindlin-2. We found that 6-month-old Kindlin-2 cKO mice have developed hypertrophic cardiomyopathy and that this pathological process can be accelerated by ISO-treatment. GATA4 expression was markedly activated in cardiac tissues of Kindlin-2 cKO mice compared to wild-type animals. Collectively, our data revealed that Kindlin-2 suppresses GATA4 expression by triggering histone H3K9 methylation in part and protects heart from pathological hypertrophy.