Ten-Eleven Translocation Proteins Modulate the Response to Environmental Stress in Mice
Ten-Eleven Translocation Proteins Modulate the Response to Environmental Stress in Mice
复制标题
十一号染色体易位蛋白调节小鼠对环境应激的反应
DOI：
10.1016/j.celrep.2018.11.061
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发表时间：
2018-12-11
期刊：
影响因子：
8.8
通讯作者：
Jin, Peng
中科院分区：
文献类型：
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作者：
Cheng, Ying;Sun, Miao;Jin, Peng
5-羟甲基胞嘧啶（5-hydroxymethylcytosine, 5hmC）富集于大脑中，是一种重要的DNA修饰。然而，5hmC及其撰写者Tet蛋白在应激反应中的作用尚未被阐明。在这里，我们发现慢性约束应激（CRS）在小鼠中诱导抑郁样行为，并导致前额皮质（PFC）减少5hmC。我们发现Tet1 （Tet1 KO）的缺失导致对CRS的抗性，而Tet2 （Tet2 KO）的缺失增加了小鼠对CRS的易感性。全基因组5hmC分析鉴定了表型相关的应激诱导的动态羟甲基化位点（PA-SI-DhMLs），这些位点富含缺氧诱导因子（HIF）结合基序。我们证明了CRS诱导的TET1和HIF1 α之间的物理相互作用，并揭示了CRS下HIF1 α结合的增加与si - dhml有关。这些结果表明TET1可能通过与HIF1 α相互作用来调节应激诱导反应。
5-hydroxymethylcytosine (5hmC) is enriched in brain and has been recognized as an important DNA modification. However, the roles of 5hmC and its writers, ten-eleven translocation (Tet) proteins, in stressinduced response have yet to be elucidated. Here, we show that chronic restraint stress (CRS) induced depression-like behavior in mice and resulted in a 5hmC reduction in prefrontal cortex (PFC). We found that loss of Tet1 (Tet1 KO) led to resistance to CRS, whereas loss of Tet2 (Tet2 KO) increased the susceptibility of mice to CRS. Genome-wide 5hmC profiling identified the phenotype-associated stress-induced dynamically hydroxymethylated loci (PA-SI-DhMLs), which are strongly enriched with hypoxia-induced factor (HIF) binding motifs. We demonstrated the physical interaction between TET1 and HIF1 alpha induced by CRS and revealed that the increased HIF1 alpha binding under CRS is associated with SI-DhMLs. These results suggest that TET1 could regulate stress-induced response by interacting with HIF1 alpha.