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

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<jats:title>SUMMARY</jats:title> <jats:p>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.</jats:p> <jats:sec> <jats:title>HIGHLIGHTS</jats:title> <jats:p> <jats:list list-type="order"> <jats:list-item> <jats:p>KDM7A and UTX cooperatively control NF-κB-dependent transcription in vascular endothelial cells.</jats:p> </jats:list-item> <jats:list-item> <jats:p>Demethylation of repressive histone marks by KDM7A and UTX is critical for early inflammatory responses.</jats:p> </jats:list-item> <jats:list-item> <jats:p>KDM7A and UTX are associated with TNF-α-induced looping of super enhancers.</jats:p> </jats:list-item> <jats:list-item> <jats:p>Pharmacological inhibition of KDM7A and UTX reduces leukocyte adhesive interactions with endothelial cells in mice.</jats:p> </jats:list-item> </jats:list> </jats:p> </jats:sec>

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