Histone Methyltransferase G9a Is Required for Cardiomyocyte Homeostasis and Hypertrophy
Histone Methyltransferase G9a Is Required for Cardiomyocyte Homeostasis and Hypertrophy
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DOI：
10.1161/circulationaha.117.028561
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发表时间：
2017-09-26
期刊：
影响因子：
37.8
通讯作者：
Condorelli, Gianluigi
中科院分区：
文献类型：
--
作者：
Papait, Roberto;Serio, Simone;Condorelli, Gianluigi
背景：心肌细胞正确的基因表达程序是心脏正常功能的基础。这一变化可能导致心脏稳态的丧失，引发心脏功能障碍。虽然一些组蛋白甲基转移酶在心脏发育过程中建立出生后心肌细胞转录程序的作用已被证明，这类表观遗传酶的功能在很大程度上是未开发的成人心脏。在这项研究中，我们研究了G9 a/Ehmt 2的作用，G9 a/Ehmt 2是一种组蛋白甲基转移酶，定义了一个抑制性表观遗传标记，在定义心肌细胞稳态和心肌肥大的转录程序中。我们研究了G9 a在正常和应激心肌细胞中的功能，使用了一种条件性的心脏特异性G9 a基因敲除小鼠，一种特异性G9 a抑制剂，和高通量的方法来研究表观基因组（染色质免疫沉淀测序）和转录组（RNA测序）;传统方法用于评估心脏功能和心血管疾病。我们发现，G9 a是成年心脏中心肌细胞稳态所必需的，通过H3赖氨酸9的二甲基化介导调节心肌细胞功能的关键基因的抑制，与zeste增强子同源物2的相互作用，多梳抑制复合物2的催化亚基，以及通过与该转录因子形成复合物的MEF 2C依赖性基因表达。发现G9 a-MEF 2C复合物也是维持成人心脏中发育基因沉默所需的异染色质所必需的。此外，G9 a通过抑制antihypertrophic genes.CONCLUSIONS：两者合计，我们的研究结果表明，G9 a编排在生理和病理条件下的心肌细胞中的关键表观遗传变化，从而为与这些机制失调相关的心脏病理提供了新的治疗途径。
BACKGROUND: Correct gene expression programming of the cardiomyocyte underlies the normal functioning of the heart. Alterations to this can lead to the loss of cardiac homeostasis, triggering heart dysfunction. Although the role of some histone methyltransferases in establishing the transcriptional program of postnatal cardiomyocytes during heart development has been shown, the function of this class of epigenetic enzymes is largely unexplored in the adult heart. In this study, we investigated the role of G9a/Ehmt2, a histone methyltransferase that defines a repressive epigenetic signature, in defining the transcriptional program for cardiomyocyte homeostasis and cardiac hypertrophy.METHODS: We investigated the function of G9a in normal and stressed cardiomyocytes with the use of a conditional, cardiacspecific G9a knockout mouse, a specific G9a inhibitor, and high-throughput approaches for the study of the epigenome (chromatin immunoprecipitation sequencing) and transcriptome (RNA sequencing); traditional methods were used to assess cardiac function and cardiovascular disease.RESULTS: We found that G9a is required for cardiomyocyte homeostasis in the adult heart by mediating the repression of key genes regulating cardiomyocyte function via dimethylation of H3 lysine 9 and interaction with enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, and MEF2C-dependent gene expression by forming a complex with this transcription factor. The G9a-MEF2C complex was found to be required also for the maintenance of heterochromatin needed for the silencing of developmental genes in the adult heart. Moreover, G9a promoted cardiac hypertrophy by repressing antihypertrophic genes.CONCLUSIONS: Taken together, our findings demonstrate that G9a orchestrates critical epigenetic changes in cardiomyocytes in physiological and pathological conditions, thereby providing novel therapeutic avenues for cardiac pathologies associated with dysregulation of these mechanisms.