TET2介导的羟甲基化表观修饰参与抑郁行为中神经再生调控

So far, there are 320 million patients with major depression in the world. Due to the high rate of suicide and disability, major depression is becoming a serious public problem. Depression is a complex disease, which is thought to be caused by the interaction of genetic and environmental factors. A large number of studies confirmed that DNA methylation caused by environmental factors is involved in the pathogenesis of depression. Hydroxylmethylation is a novel DNA modification with the de-methylation effect; however, its role in the pathogenesis of depression has not been explored. In our previous work, we found that the hydroxylmethylation modification was reduced in the brain of chronically stressed mice and the knockout of TET2, a catalytic enzyme of hydroxylmethylation reaction, caused a depression-like phenotype. TET2 is an important regulatory protein that is involved in leukemia and tumor cell proliferation. Therefore, this study will use transgenic mice and hydroxylmethylation sequencing techniques to examine the role of TET2-mediated DNA hydroxylmethylation in neurogenesis and to explore whether the hydroxylmethylation of Cend1 is involved in the regulation of neurogenesis. The completion of this project will explain the important role of DNA hydroxylmethylation in the mechanism of depression and provide a new clue for the treatment of major depression.

最新数据统计表明全世界抑郁症患者已达3.2亿，是一个日益严重社会问题。抑郁症是一种复杂性疾病，其机制不清，被认为是遗传因素与环境因素相互作用的结果。环境因素通过表观遗传改变而影响抑郁易感基因表达而发挥作用；环境因素引起的DNA甲基化被证实参与了抑郁发生机制。羟甲基化(5hmC)是新发现的具有去甲基化作用的表观修饰，我们前期发现抑郁样小鼠脑内5hmC修饰降低；5hmC催化酶TET2敲除具有抑郁样表型。作为白血病发生和肿瘤细胞增殖的重要调控蛋白，TET2敲除如何通过影响基因5hmC修饰而引起抑郁发生尚未见报道。本课题将利用基因敲除小鼠和5hmC测序等技术深入研究TET2介导的5hmC修饰在抑郁发生及神经再生中的作用；并探讨Cend1基因5hmC修饰是否参与神经再生调控。本项目成果将阐明5hmC修饰在抑郁发生中的调控及其机制，为靶向调控去甲基化治疗抑郁症提供理论和实验基础。

世界卫生组织统计数据表明抑郁症已经成为日益严重的世界性社会问题。目前抑郁症发病机制尚不清楚，认为是遗传因素与环境因素相互作用的结果，环境因素通过表观遗传改变而影响抑郁易感基因表达而发挥作用。我们前期发现表观遗传催化酶TET2基因敲除小鼠具有抑郁样表型，但TET2敲除引起抑郁发生并不清楚。本课题研究了TET2介导的羟甲基化(5hmC)修饰在抑郁发生中的重要作用和机制。本课题研究发现环境应激后TET2介导的5hmC修饰影响了相关抑郁基因的表达并在抑郁行为发生中其中重要作用；TET2基因敲除小鼠造成海马的神经再生障碍，而调控神经再生的重要基因Cend1在应激后5hmC修饰显著降低及蛋白表达减少；本研究证实TET2能够结合到Cend1启动子区域并参与启动子区域的5hmC修饰。另外在抑郁症患者外周血5hmC测序分析发现6个基因可能是抑郁症潜在生物学标记物。因此本课题解释了环境应激诱导的表观遗传修饰特别是TET2介导的表观遗传修饰在抑郁发生中的重要机制，为靶向表观遗传修饰的抑郁治疗提供了理论依据和向临床转化提供了有力的数据支持。本项目的完成发表了多篇研究论文并促进了研究生培养。