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

Authors: Zhang, Q.; Zhao, K.; Shen, Q.; Han, Y.; Gu, Y.; Li, X.; Zhao, D.; Liu, Y.; Wang, C.; Zhang, X.; Su, X.; Liu, J.; Ge, W.; Levine, R. L.; Li, N.; Cao, X.
Article Title: Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6
Abstract: Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered. 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. ©2015 Macmillan Publishers Limited. All rights reserved.
Keywords: controlled study; unclassified drug; human cell; promoter region; nonhuman; animal cell; mouse; phenotype; gene targeting; mus; dendritic cell; transcription initiation; animal experiment; inflammation; transcription factor; in vivo study; in vitro study; wild type; dna methylation; dna; histone; chromatin; gene repression; interleukin 6; gene loss; lipopolysaccharide; cytokine production; innate immunity; bone marrow cell; deacetylation; histone deacetylation; histone deacetylase 2; receptor upregulation; mediator; septic shock; peritoneum macrophage; dextran sulfate; i kappa b kinase epsilon; dioxygenase; human; priority journal; article; tet2 protein; bone marrow derived macrophage; experimental colitis
Journal Title: Nature
Volume: 525
Issue: 7569
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2015-09-17
Start Page: 389
End Page: 393
Language: English
DOI: 10.1038/nature15252
PROVIDER: scopus
PUBMED: 26287468
PMCID: PMC4697747
Notes: Export Date: 2 October 2015 -- Source: Scopus
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  1. Ross Levine
    469 Levine