KDM4B histone demethylase and G9a regulate expression of vascular adhesion proteins in cerebral microvessels.
Intercellular adhesion molecule 1 (ICAM1) mediates the adhesion and transmigration of leukocytes across the endothelium, promoting inflammation. We investigated the epigenetic mechanism regulating ICAM1 expression. The pro-inflammatory cytokine TNF-α dramatically increased ICAM1 mRNA and protein levels in human brain microvascular endothelial cells and mouse brain microvessels. Chromatin immunoprecipitation revealed that TNF-α reduced methylation of histone H3 at lysines 9 and 27 (H3K9 and H3K27), well-known residues involved in gene suppression. Inhibition of G9a and EZH2, histone methyltransferases responsible for methylation at H3K9 and H3K27, respectively as well as G9a overexpression demonstrated the involvement of G9a in TNF-α-induced ICAM1 expression and leukocyte adhesion and transmigration. A specific role for KDM4B, a histone demethylase targeting H3K9me2, in TNF-α-induced ICAM1 upregulation was validated with siRNA. Moreover, treating mice with a KDM4 inhibitor ML324 blocked TNF-α-mediated neutrophil adhesion. Similarly, TNF-α-induced VCAM1 expression was suppressed by G9a overexpression and KDM4B knockdown. Collectively, we demonstrated that modification of H3K9me2 by G9a and KDM4B regulates expression of vascular adhesion molecules, and that depletion of these proteins or KDM4B reduces inflammation-induced leukocyte extravasation. Thus, blocking ICAM1 or KDM4B could offer a novel therapeutic opportunity treating brain diseases.
Department of Nanobiomedical Science &BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 330-714, South Korea.
Ji-Young
JY
Choi
Department of Nanobiomedical Science &BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 330-714, South Korea.
Sang-Sun
SS
Yoon
Department of Pharmacology, College of Pharmacy, Dankook University, Cheonan 330-714, South Korea.
Sang-Eun
SE
Kim
Department of Nanobiomedical Science &BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 330-714, South Korea.|Department of Pharmacology, College of Pharmacy, Dankook University, Cheonan 330-714, South Korea.
Sangmee
S
Ahn Jo
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D057890:Epigenomics; D005786:Gene Expression Regulation / Q000187:drug effects; D006649:Histocompatibility Antigens / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D055806:Microvessels / Q000378:metabolism*; D008954:Models, Biological; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D006649:Histocompatibility Antigens; D006657:Histones; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase