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

By Qian Zhang, K. Zhao, Qicong Shen, Yanmei Han, Yan Gu, Xia Li, Dezhi Zhao, Yiqi Liu, Chunmei Wang, Xiang Zhang and 6 more. Nature, 2015

736 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2ee8ea2d9e870df63c430120ef9193ccfe1c63be

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Citations in the corpus

• The JAK/STAT signaling pathway: from bench to clinic (2021, background): “Previous studies showed that activated STAT3 proteins could promote cytokine production in a variety of cancers.(244) Using a JAK2 inhibitor to treat mice with MPN resulted in reduced cytokine levels and attenuated systemic symptoms.”
• Macrophages in immunoregulation and therapeutics (2023, background): “Similarly, TET deficiency by modulating DNA methylation and hydroxymethylation for activating macrophages with high IL-6 and IL-1B expression is also documented.(230) Leishmania donovani infection induces methylation changes at the 443 CpG site in host macrophages, suppressing innate immunity and th”
• Clonal hematopoiesis in human aging and disease (2019, positive): “One group found that mice deficient in Tet2 developed more severe inflammation in several tissues upon challenge with bacterial endotoxin, and this was partially explained by increased expression of the proinflammatory cytokine Il6 in dendritic cells and macrophages (92).”
• Tet2-mediated Clonal Hematopoiesis Accelerates Heart Failure through a Mechanism Involving the IL-1β/NLRP3 Inflammasome (2018, background): “the oxidation of 5-methylcytosine, but involves changes in the recruitment of histone deacetylase to the IL-1β promoter (19,46).”
• Role of TET enzymes in DNA methylation, development, and cancer (2016, background): “induced stimulation in a histone deacetylase (HDAC)-dependent manner (Zhang et al. 2015).”