Letter | Published:

Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6

Nature volume 525, pages 389393 (17 September 2015) | Download Citation

Abstract

Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status1. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members2, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered3. However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. IκBζ, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IκBζ at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

The deep sequencing data have been deposited in the Gene Expression Omnibus under accession number GSE69256.

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Acknowledgements

This work was supported by the National Key Basic Research Program of China (2013CB530503) and the National Natural Science Foundation of China (31200654, 31390431, 81230074, 81123006).

Author information

Author notes

    • Qian Zhang
    • , Kai Zhao
    • , Qicong Shen
    •  & Yanmei Han

    These authors contributed equally to this work.

Affiliations

  1. National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China

    • Qian Zhang
    • , Kai Zhao
    • , Xia Li
    • , Dezhi Zhao
    • , Chunmei Wang
    • , Wei Ge
    •  & Xuetao Cao
  2. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai 200433, China

    • Qian Zhang
    • , Qicong Shen
    • , Yanmei Han
    • , Yan Gu
    • , Yiqi Liu
    • , Xiang Zhang
    • , Xiaoping Su
    • , Juan Liu
    • , Nan Li
    •  & Xuetao Cao
  3. Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer, New York, New York 10016, USA

    • Ross L. Levine

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Contributions

Q.Z., K.Z., Q.S. and Y.H. performed the experiments, analysed the data and contributed equally for the whole study. Y.G., X.L., D.Z., Y.L., C.W., X.Z., X.S., J.L., W.G. and N.L. provided reagents and performed experiments; RL.L. provided Tet2 KO mice. X.C. and Q.Z. analysed the data and wrote the manuscript. X.C. designed and supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Xuetao Cao.

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    Supplementary Information

    This file contains Supplementary Figure 1, which shows the full scans of the blots and gels.

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DOI

https://doi.org/10.1038/nature15252

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