TET1介导的DNA去甲基化在扩张型心肌病中的作用

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy with a worse prognosis. Approximately 50% of the patients with DCM die after the onset of the disease. Currently, the mechanisms of DCM pathogenesis were poorly understood. Our preliminary data showed that the amount of 5-hmC (5-hydromethyl cytocine, 5-hmC), a critical intermediate of DNA methylation, was significantly increased in the heart tissues from the patients with DCM as compared to normal control. Moreover, Ten-Eleven Translocation 1(TET1) protein, a critical methylcytosine dioxygenase to catalyze the formation of 5-hmc TET1, was significantly up-regulated concomitantly. Intriguingly, by statistical analysis, we demonstrated that the TET1 protein expression was negatively correlated with the survival time of the patients with DCM, indicating the potential role of TET1 in the pathogenesis and development of DCM. Based on these exciting preliminary data, we aim to unravel the role of TET1 in DCM associated myocardial remodeling, the targets gene of TET1 and the LncRNA guiding the localization of TET1 on its target genes by employing the state-of-the-art high throughput sequencing technology. Taken together, our innovative project may provide a novel avenue to decode the pathogenesis of DCM and even discover new biomarkers for early detection and potential targets for drug development.

扩张型心肌病（Dilated Cardiomyopathy，DCM）是最常见的原发性心肌病，大约有50%的患者在2-5年内死亡，但DCM的发病机制却尚未清楚。我们的预实验结果首次发现DCM患者心脏组织与正常人的相比，DNA去甲基化的重要中间产物5-羟甲基胞嘧啶（5-hydromethyl cytocine，5-hmC）含量显著增加，且催化5-hmC生成的关键酶TET1在DCM心脏的表达也显著升高，TET1表达与DCM患者的生存预后呈负相关，提示TET1介导的DNA去甲基化可能在DCM发生和发展中起重要作用。本项目在这些前期研究的基础上，拟在动物模型上进一步明确TET1在DCM心肌重构中的作用，并通过高通量测序技术寻找TET1介导DCM心肌重构的关键靶基因以及挖掘介导TET1定位到靶基因上的长非编码RNA。这一探索旨为DCM的发病机制提供新的科学依据，并有望发现新的生物标记物和潜在治疗靶点。

扩张型心肌病（DCM）是最严重影响人类健康的原发性心肌病，大约有50%的患者在2-5年内死亡，但DCM的发病机制却尚未清楚。TET1是实现DNA去甲基化的关键酶，可以使由于CpG启动子甲基化沉默的基因重新表达，在DCM心脏中TET1的表达显著升高，TET1表达与DCM患者的生存预后呈负相关，进一步，我们在DCM动物模型发现TET1对DCM有重构作用，并通过高通量测序技术发现TET1介导DCM心肌重构的关键靶基因RASSF1A，我们还通过亚硫酸盐测序发现DCM小鼠心肌组织中RASSF1A启动子甲基化的水平明显升高，因此，我们推测RASSF1A启动子甲基化参与了DCM的心肌纤维的分子调控，这提示异常RASSF1A甲基化的逆转和RASSF1A过表达恢复转录是抑制心肌纤维化进展的新治疗靶点，可作为DCM的抗纤维化治疗策略。