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Author Notes:

Correspondence: xingshunxu@suda.edu.cn (X.X.), peng.jin@emory.edu (P.J.).

Y.C., X.X., and P.J. conceived the project.

Y.C. performed the experiments.

Y.C., L.C., B.Y., Z.L., and H.W. performed the bioinformatics analyses.

L.L., Y.L., and J.C. constructed 5hmC sequencing (5hmC-seq), ChIP-seq, and RNA-seq libraries.

M.S., Z.M., Z.W., N.X., and L.H. helped with behavioral assays and mouse maintenance.

Y.C., X.X., and P.J. wrote the manuscript.

The authors thank Deborah Cook for critical reading of the manuscript.

The authors declare no competing interests.


Research Funding:

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.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • TET1
  • DNA

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

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Journal Title:

Cell Reports


Volume 25, Number 11


, Pages 3194-+

Type of Work:

Article | Final Publisher PDF


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.

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© 2018 The Author(s)

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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