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 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.

The Atypical Inhibitor of NF-κB, IκBζ, Controls Macrophage Interleukin-10 Expression

“…The histone deacetylase HDAC11 has been found to inhibit IL-10 expression (41), whereas phosphorylation of histone H3 at serine 10 is needed for transcriptional activation of the Il10 promoter (42). A recent study found that IB recruits the epigenetic modifier Tet2 to selective promoter regions independent of DNA meth- ylation (43). IB further mediates chromatin remodeling by recruiting the SWI/SNF complex to target genes, thereby enhancing promoter accessibility (32).…”

Cellular and molecular regulation of innate inflammatory responses

“…51 During the late phase of inflammatory response, induction of de novo 5-hydroxymethylation upstream of the Il6 locus by a methylcytosine dioxygenase TET2 recruits HDAC2 to inhibit Il6 transcription via histone deacetylation and is critical for termination of the high transcription of Il6. 52 It will be intriguing to further investigate the molecular mechanisms and physiological relevance of epigenetic modification at different phases of innate inflammatory response.…”

Effect of cytostatic proline rich polypeptide-1 on tumor suppressors of inflammation pathway signaling in chondrosarcoma

“…TET1 and TET2 act predominantly as tumor suppressors. Re-introduction and overexpression of these proteins is able to restore the 5hmC content, and to suppress invasion and growth in certain tumors (37)(38)(39)(40)(41). A previous report revealed that a deficiency in SOCS3 may promote tumor development, since it has tumor suppressor functions in numerous cancer cell types (29).…”