Beijing Engineering Research Center for Experimental Animal Models of Human Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Lab Invest. 2020 Jul;100(7):974-985. doi: 10.1038/s41374-020-0402-y. Epub 2020 Feb 12.
Novel molecular mechanisms of the pathophysiology of heart failure (HF) are continuously being discovered, including epigenetic regulation. Among epigenetic marks, the role of DNA hypomethylation in shaping heart morphology and function in vivo and the pathogenesis of cardiomyopathy and/or HF, especially in adults, has not been clearly established. Here we show that the strong expression of DNA methyltransferase 1 (Dnmt1) is obviously downregulated in the WT adult rat heart with age. By contrast, the expression of Dnmt1 is upregulated suddenly in heart tissues from pressure overload-induced HF mice and adriamycin-induced cardiac injury and HF mice, consistent with the increased expression of Dnmt1 observed in familial hypertrophic cardiomyopathy (FHCM) patients. To further assess the role of Dnmt1, we generated myocardium-specific Dnmt1 knockout (Dnmt1 KO) rats using CRISPR-Cas9 technology. Echocardiographic and histopathological examinations demonstrated that Dnmt1 deficiency is associated with resistance to cardiac pathological changes and protection at the global and organization levels in response to pathological stress. Furthermore, Dnmt1 deficiency in the myocardium restricts the expressional reprogramming of genes and activates pathways involved in myocardial protection and anti-apoptosis in response to pathological stress. Transcriptome and genome-wide DNA methylation analyses revealed that these changes in regulation are linked to alterations in the methylation status of genes due to Dnmt1 knockout. The present study is the first to investigate in vivo the impact of genome-wide cardiac DNA methyltransferase deficiency on physiological development and the pathological processes of heart tissues in response to stress. The exploration of the role of epigenetics in the development, modification, and prevention of cardiomyopathy and HF is in a very preliminary stage but has an infinite future.
心力衰竭（HF）的病理生理学的新分子机制不断被发现，包括表观遗传调控。在表观遗传标记中，DNA 低甲基化在塑造体内心脏形态和功能以及心肌病和/或 HF 的发病机制中的作用，特别是在成人中，尚未得到明确证实。在这里，我们发现随着年龄的增长，WT 成年大鼠心脏中的 DNA 甲基转移酶 1（Dnmt1）的强表达明显下调。相比之下，压力超负荷诱导的 HF 小鼠和阿霉素诱导的心脏损伤和 HF 小鼠的心脏组织中 Dnmt1 的表达突然上调，与家族性肥厚型心肌病（FHCM）患者观察到的 Dnmt1 表达增加一致。为了进一步评估 Dnmt1 的作用，我们使用 CRISPR-Cas9 技术生成了心肌特异性 Dnmt1 敲除（Dnmt1 KO）大鼠。超声心动图和组织病理学检查表明，Dnmt1 缺失与心脏病理变化的抵抗以及对病理应激的全局和组织水平的保护有关。此外，心肌中 Dnmt1 的缺失限制了基因表达的重新编程，并激活了与病理应激下心肌保护和抗凋亡相关的途径。转录组和全基因组 DNA 甲基化分析表明，这些调节变化与由于 Dnmt1 敲除导致的基因甲基化状态的改变有关。本研究首次在体内研究了基因组范围的心脏 DNA 甲基转移酶缺乏对生理发育和应激反应中心脏组织病理过程的影响。探索表观遗传学在心肌病和 HF 的发展、修饰和预防中的作用还处于非常初级的阶段，但具有无限的未来。
