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

Abstract

C.K.G.), kanki@lsbm.org (Y.K.) SUMMARY 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. (150 words) KEYWORDS Inflammation, atherosclerosis, histone modification enzyme, repressive histone mark, super enhancer, chromatin architecture, chromatin conformation change HIGHLIGHTS 1. KDM7A and UTX cooperatively control NF-κB-dependent transcription in vascular endothelial cells. 2. Demethylation of repressive histone marks by KDM7A and UTX is critical for early inflammatory responses. 3. KDM7A and UTX are associated with TNF-α-induced looping of super enhancers. 4. Pharmacological inhibition of KDM7A and UTX reduces leukocyte adhesive interactions with endothelial cells in mice.

UTX/KDM6A Deletion Promotes Recovery of Spinal Cord Injury by Epigenetically Regulating Vascular Regeneration

“…UTX has been functionally linked to many physical and pathological processes, including embryonic development, 39,40 tumor progression, [41][42][43][44] inflammation, 45 and stem cell differentiation 46,47 by H3K27 demethylation-dependent or -independent gene transcription. Although UTX was shown to be required for nuclear factor kB (NF-kB)-dependent inflammatory response of ECs, 48 the regenerative regulation mediated by UTX in SCI is still unclear. We first examined the changes of several key epigenetic regulators post SCI, and we found that the mRNA level of UTX increased significantly post SCI, whereas the changes of other epigenetic factors are variable at different time points post SCI.…”

The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells

“…These observations also suggest that KDM7A and RHOJ may possess mutually independent prometastatic functions. Prior studies, based on either single-locus or genome-wide gene expression analysis, have suggested that KDM7A is involved in the regulation of target genes downstream of the NF-κB pathway ( Higashijima et al, 2020 ) and the Wnt/β-catenin pathway ( Yang et al, 2019a ; Liu et al, 2020 ), which allude to a broader promalignancy mechanism. Small-molecule inhibitors of KDM7A have been discovered although their therapeutic potentials in breast cancer have yet to be explored ( Gerken et al, 2017 ).…”

YBX1 Indirectly Targets Heterochromatin-Repressed Inflammatory Response-Related Apoptosis Genes through Regulating CBX5 mRNA

“…Further evidence is given by TNFα mediated inflammation, upon which rapid removal of repressive histone marks H3K9me2/me3 and H3K27me3 leads to activation of Nf-kB and other inflammatory signaling cascades via KDM7A and UTX [ 54 ]. This is in line with our hypothesis of gene induction of heterochromatin repressed inflammatory signaling genes.…”