Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells

Autor: Higashijima, Y., Matsui, Y., Shimamura, T., Nakaki, R., Nagai, N., Tsutsumi, S., Abe, Y., Link, V. M., Osaka, M., Yoshida, M., Watanabe, R., Tanaka, T., Taguchi, A., Miura, M., Ruan, X., Li, G., Inoue, T., Nangaku, M., Kimura, Hiroshi, Furukawa, T., Aburatani, H., Wada, Y., Ruan, Y., Glass, C. K., Kanki, Y.
Rok vydání: 2020
Předmět:
Male
Jumonji Domain-Containing Histone Demethylases
Endothelial Cells/cytology/*immunology/metabolism
repressive histone mark
endothelial dysfunction
Histones
Chromosome conformation capture
Mice
chromatin conformation
0302 clinical medicine
Gene expression
Histone methylation
Gene Regulatory Networks
Histone Demethylases
Tumor Necrosis Factor-alpha/metabolism
0303 health sciences
biology
General Neuroscience
Articles
Cell biology
Histone
histone demethylase
Tumor necrosis factor alpha
Jumonji Domain-Containing Histone Demethylases/*metabolism
Lysine/metabolism
Signal Transduction
super enhancer
Histone Demethylases/*metabolism
Methylation
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Histone H3
microRNA
Cell Adhesion
Human Umbilical Vein Endothelial Cells
Animals
Humans
Enhancer
Molecular Biology
030304 developmental biology
General Immunology and Microbiology
Tumor Necrosis Factor-alpha
Lysine
Endothelial Cells
MicroRNAs
Gene Expression Regulation
MicroRNAs/*genetics
biology.protein
Histones/chemistry/*metabolism
030217 neurology & neurosurgery
Zdroj: EMBO J
ISSN: 1460-2075
0261-4189
Popis: 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 (KDM7A) and 6A (UTX) play crucial roles in tumor necrosis factor (TNF)‐α signaling in endothelial cells (ECs), where they are regulated by a novel TNF‐α‐responsive microRNA, miR‐3679‐5p. TNF‐α rapidly induces co‐occupancy of KDM7A and UTX at nuclear factor kappa‐B (NF‐κB)‐associated elements in human ECs. KDM7A 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 KDM7A and UTX recruitments. Simultaneous pharmacological inhibition of KDM7A 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 KDM7A and UTX is essential for NF‐κB‐dependent regulation of genes that control inflammatory responses of ECs.
Databáze: OpenAIRE
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