Epigenetic regulation of phosphodiesterase 4d in restrictive cardiomyopathy mice with cTnI mutations.
Epigenetic regulation of phosphodiesterase 4d in restrictive cardiomyopathy mice with cTnI mutations.
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cTnI 突变限制性心肌病小鼠磷酸二酯酶 4d 的表观遗传调控。
DOI：
10.1007/s11427-018-9463-9
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Tian Jie
中科院分区：
文献类型：
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作者：
Zhao Weian;Wu Xiaoqi;Wang Zhiyuan;Pan Bo;Liu Lifei;Liu Lingjuan;Huang Xupei;Tian Jie
表观遗传调控在疾病发展中起重要作用。在这项研究中，我们研究了cTnI 193His突变的限制性心肌病小鼠的表观遗传调控。我们的研究结果表明，磷酸二酯酶（PDEs） 4d在这些小鼠的心脏中下调。进一步的研究表明，表观遗传修饰与组蛋白3赖氨酸4和赖氨酸9的乙酰化增强有关，而在PDE4d基因启动子区域附近的组蛋白中，组蛋白3赖氨酸4的三甲基化减少。在cTnI193His转基因心脏中，组蛋白转甲基化酶SMYD1和组蛋白去乙酰化酶HDAC1在基因启动子区域的结合水平升高。我们利用免疫荧光标记法在心肌细胞核中发现了cTnI存在的证据，Western blotting进一步证实了在心脏细胞核中可以检测到野生型和突变型cTnI。此外，还观察到cTnI与SMYD1或cTnI与HDAC1之间的相互作用。在培养的心肌细胞中过表达突变的cTnI可降低PDE4d的表达。我们的数据表明，cTnI突变引起的RCM小鼠PDE4d表达下降可能与表观遗传调控有关，即组蛋白乙酰化和甲基化，cTnI可能通过与心脏中HDAC1和SMAD1的相互作用参与了这一过程。
Epigenetic regulations play an important role in disease development. In this study, we have investigated epigenetic regulations in restrictive cardiomyopathy mice with cTnI 193His mutation. Our results demonstrated that phosphodiesterase (PDEs) 4d was down-regulated in the heart of these mice. Further studies showed that the epigenetic modifications were associated with enhanced acetylation of histone 3 lysine 4 and lysines 9, whereas tri-methylation of histone 3 lysine 4, were decreased in histones near the PDE4d gene promoter regions. The binding levels of histone transmethylase SMYD1 and histone deacetylase HDAC1 were increased in the gene promoter regions in cTnI193His transgenic hearts. Using immune-fluorescent labeling we found an evidence of cTnI existence in the nucleus of cardiomyocytes and Western blotting further confirmed that both wild type and mutated cTnI could be detected in the cell nucleus of the hearts. Furthermore, an interaction between cTnI and SMYD1, or cTnI and HDAC1 was observed. Overexpression of the mutated cTnI in cultured cardiomyocytes reduced the expression of PDE4d. Our data suggest that the decrease of PDE4d expression in RCM mice caused by cTnI mutations may be related to epigenetic regulation, i.e., histone acetylation and methylation, and cTnI might be involved in this procedure via an interaction with HDAC1 and SMAD1 in the hearts.