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Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells
Author(s) -
Higashijima Yoshiki,
Matsui Yusuke,
Shimamura Teppei,
Nakaki Ryo,
Nagai Nao,
Tsutsumi Shuichi,
Abe Yohei,
Link Verena M,
Osaka Mizuko,
Yoshida Masayuki,
Watanabe Ryo,
Tanaka Toshihiro,
Taguchi Akashi,
Miura Mai,
Ruan Xiaoan,
Li Guoliang,
Inoue Tsuyoshi,
Nangaku Masaomi,
Kimura Hiroshi,
Furukawa Tetsushi,
Aburatani Hiroyuki,
Wada Youichiro,
Ruan Yijun,
Glass Christopher K,
Kanki Yasuharu
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103949
Subject(s) - biology , demethylation , microbiology and biotechnology , genetics , dna methylation , gene expression , gene
Histone H3 lysine‐9 di‐methylation (H3K9me2) and lysine‐27 tri‐methylation (H3K27me3) are linked to repression of gene expression, but the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. Here, we report that lysine demethylases 7A ( KDM 7A) and 6A ( UTX ) play crucial roles in tumor necrosis factor ( TNF )‐α signaling in endothelial cells ( EC s), where they are regulated by a novel TNF ‐α‐responsive micro RNA , miR‐3679‐5p. TNF ‐α rapidly induces co‐occupancy of KDM 7A and UTX at nuclear factor kappa‐B ( NF ‐κB)‐associated elements in human EC s. KDM 7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and are both required for activation of NF ‐κB‐dependent inflammatory genes. Chromosome conformation capture‐based methods furthermore uncover increased interactions between TNF ‐α‐induced super enhancers at NF ‐κB‐relevant loci, coinciding with KDM 7A and UTX recruitments. Simultaneous pharmacological inhibition of KDM 7A and UTX significantly reduces leukocyte adhesion in mice, establishing the biological and potential translational relevance of this mechanism. Collectively, these findings suggest that rapid erasure of repressive histone marks by KDM 7A and UTX is essential for NF ‐κB‐dependent regulation of genes that control inflammatory responses of EC s.