Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis.
Ten-eleven translocation 2 interacts with forkhead box O3 and regulates adult neurogenesis.
复制标题
10-11易位2与叉头盒O3相互作用并调节成体神经发生
DOI：
10.1038/ncomms15903
复制
发表时间：
2017-06-29
影响因子：
16.6
通讯作者：
Jin P
中科院分区：
文献类型：
--
作者：
Li X;Yao B;Chen L;Kang Y;Li Y;Cheng Y;Li L;Lin L;Wang Z;Wang M;Pan F;Dai Q;Zhang W;Wu H;Shu Q;Qin Z;He C;Xu M;Jin P
新出现的证据表明，活跃的DNA去甲基化机制在哺乳动物成体神经发生中起着重要的表观遗传作用;然而，DNA去甲基化在这一过程中的精确分子机制和关键功能参与者仍然在很大程度上未被探索。10 - 11易位（泰特）蛋白将5-甲基胞嘧啶（5 mC）转化为5-羟甲基胞嘧啶（5 hmC）及其下游衍生物。在这里，我们表明，5 hmC在成人神经干细胞（aNSCs）的分化过程中升高，Tet 2主要负责调节5 hmC的动态。Tet 2的缺失导致体外和体内aNSC增殖增加和分化减少。全基因组转录分析揭示了Tet 2在维持与神经发生相关的转录组景观中的重要表观遗传作用。从机制上讲，转录因子叉头盒O3（Foxo 3a）与Tet 2物理相互作用，并调节与aNSC增殖相关的基因的表达。这些数据共同确立了Tet 2-Foxo 3a轴在成体神经发生期间在表观遗传学上调节aNSC中的关键基因的重要作用。
Emerging evidence suggests that active DNA demethylation machinery plays important epigenetic roles in mammalian adult neurogenesis; however, the precise molecular mechanisms and critical functional players of DNA demethylation in this process remain largely unexplored. Ten–eleven translocation (Tet) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and its downstream derivatives. Here we show that 5hmC is elevated during the differentiation of adult neural stem cells (aNSCs), and Tet2 is primarily responsible for modulating 5hmC dynamics. Depletion of Tet2 leads to increased aNSC proliferation and reduced differentiationin vitroandin vivo. Genome-wide transcriptional analyses reveal important epigenetic roles of Tet2 in maintaining the transcriptome landscape related to neurogenesis. Mechanistically, transcription factor forkhead box O3 (Foxo3a) physically interacts with Tet2 and regulates the expression of genes related to aNSC proliferation. These data together establish an important role for the Tet2-Foxo3a axis in epigenetically regulating critical genes in aNSCs during adult neurogenesis.