The methyltransferase Ezh2 in microglia facilitates neuroinflammation through inhibition of Socs3

Identification: Xiao, Yichuan



The methyltransferase Ezh2 in microglia facilitates neuroinflammation through inhibition of Socs3
Yichuan Xiao1*, Jun Qin1, Gabriela Constantin2 Xingli Zhang1, Yan Wang1, Jia Yuan1
1Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 2Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy
*Corresponding author
Histone H3K27 trimethyltransferase, Ezh2 is implicated in the silencing of gene expression1,2. Rather than functions as a repressor, here we identified that microglial H3K27me3 or Ezh2 mediates toll-like receptor (TLR)-induced proinflammatory gene expression, and thereby Ezh2 depletion diminishes microglial activation and attenuates the disease severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Mechanistic characterizations indicated that Ezh2 deficiency directly stimulates Socs3 expression, and therefore enhances the Lys48-linked ubiquitination and degradation of TRAF6. As a consequence, TLR-induced MyD88 dependent NF-κB activation and the expression of proinflammatory genes in microglia are compromised in the absence of Ezh2. The functional dependence of Ezh2 for Socs3 is further illustrated by the rescue experiments, in which silencing of Socs3 restores microglial activation and rescues neuroinflammation in microglial Ezh2-deficient mice. Together, these findings establish Ezh2 as a microglial-specific mediator of neuroinflammation and highlight a previously unknown mechanism of Ezh2 function.
  1. De Santa, F., M.G. Totaro, E. Prosperini, S. Notarbartolo, G. Testa, and G. Natoli. 2007. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130:1083-1094.
  2. Wei, G., L. Wei, J. Zhu, C. Zang, J. Hu-Li, Z. Yao, K. Cui, Y. Kanno, T.Y. Roh, W.T. Watford, et al. 2009. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30:155-167.

This research was supported by the grants from the Jiangsu Provincial Key and Development Program (BE2016722), the National Natural Science Foundation of China (81571545, 81770567), European Research Council grants (695714 IMMUNOALZHEIMER and 693606 IMPEDE), and National Multiple Sclerosis Society (NMSS) of USA (RG-1501-02926).



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