Publication Date:
2015-08-20
Description:
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. IkappaBzeta, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IkappaBzeta 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697747/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697747/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Qian -- Zhao, Kai -- Shen, Qicong -- Han, Yanmei -- Gu, Yan -- Li, Xia -- Zhao, Dezhi -- Liu, Yiqi -- Wang, Chunmei -- Zhang, Xiang -- Su, Xiaoping -- Liu, Juan -- Ge, Wei -- Levine, Ross L -- Li, Nan -- Cao, Xuetao -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA173636/CA/NCI NIH HHS/ -- England -- Nature. 2015 Sep 17;525(7569):389-93. doi: 10.1038/nature15252. Epub 2015 Aug 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai 200433, China. ; Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26287468" target="_blank"〉PubMed〈/a〉
Keywords:
Acetylation
;
Animals
;
Chromatin/chemistry/genetics/metabolism
;
Colitis/enzymology/immunology/metabolism
;
DNA Methylation
;
DNA-Binding Proteins/deficiency/*metabolism
;
Dendritic Cells/cytology/metabolism
;
Down-Regulation/genetics
;
Epigenesis, Genetic
;
Female
;
HEK293 Cells
;
Histone Deacetylase 2/*metabolism
;
Histones/chemistry/metabolism
;
Humans
;
I-kappa B Proteins/metabolism
;
Inflammation/enzymology/immunology/*metabolism
;
Interleukin-6/*antagonists & inhibitors/*biosynthesis/genetics/immunology
;
Macrophages/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Promoter Regions, Genetic/genetics
;
Proto-Oncogene Proteins/deficiency/*metabolism
;
Transcription, Genetic
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
