Ten-Eleven Translocation Proteins Modulate the Response to Environmental Stress in Mice

• Type of Material: Article
• Authors: Ying Cheng, Emory University; Miao Sun, Soochow University; Li Chen, Emory University; Yujing Li, Emory University; Li Lin, Emory University; Bing Yao, Emory University; Ziyi Li, Emory University; Zhiqin Wang, Emory University; Jack Chen, Emory University; Zhigang Miao, Soochow University; Ning Xin, Soochow University; Luoxiu Huang, Emory University; Emily Allen, Emory University; Hao Wu, Emory University; Xingshun Xu, Soochow University; Peng Jin, Emory University
• Language: English
• Date: 2018-12-11
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2018.11.061
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 25
• Issue: 11
• Start Page: 3194
• End Page: +
• Grant/Funding Information: This work was supported by grants from the National Key R&D Program of China (2017YFE0103700) and the National Natural Science Foundation of China (81120108011 and 81771454) to X.X. and in part by NIH grants (NS051630, MH102690, NS097206, and AG052476 to P.J.).
• Keywords: MODEL; DNA; LIFE EVENTS; HISTONE METHYLATION; Cell Biology; TET1; DEPRESSION; 5-HYDROXYMETHYLCYTOSINE; Science & Technology; Life Sciences & Biomedicine; RESTRAINT STRESS; 5-METHYLCYTOSINE; SEROTONIN TRANSPORTER GENE
• Research Categories: Biology, Genetics; Biology, Biostatistics; Biology, Cell

Abstract

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 stress-induced 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 HIF1α induced by CRS and revealed that the increased HIF1α binding under CRS is associated with SI-DhMLs. These results suggest that TET1 could regulate stress-induced response by interacting with HIF1α. The roles of 5-hydroxymethylcytosine (5hmC) and its writers, Tet proteins, in stress-induced response remain unclear. Cheng et al. show that Tet1 knockout mice exhibit resistance, whereas Tet2 knockout mice have increased susceptibility to stress. Biochemical and genome-wide analyses suggest that Tet1 could regulate stress-induced response by interacting with Hif1α.