Nov 11, 2018

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

BioRxiv : the Preprint Server for Biology
Yoshiki HIGASHIJIMAYasuharu KANKI

Abstract

Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are generally linked to gene repression. However, the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. We found that tumor necrosis factor (TNF)-α rapidly induces the co-occupancy of lysine demethylases 7A (KDM7A) and 6A (UTX) with nuclear factor kappa-B (NF-κB) recruited elements in human endothelial cells. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and both are required for activation of NF-κB-dependent inflammatory genes. Chromosome conformation capture-based methods demonstrated increased interactions between TNF-α-induced super enhancers at NF-κB-relevant loci, coinciding with KDM7A- and UTX-recruitment. Simultaneous inhibition of KDM7A and UTX significantly reduced 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 endothelial cells.

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Mentioned in this Paper

Leukocyte Cell-cell Adhesion
Histone antigen
Tumor Necrosis Factor-alpha
Protein Methylation
Genes
Histone Methylation
Regulation of Biological Process
Area 6a of Vogts
KDM7A
TNF

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