Regulation of angiogenesis by histone chaperone HIRA-mediated incorporation of lysine 56-acetylated histone H3.3 at chromatin domains of endothelial genes.
Angiogenesis is critically dependent on endothelial cell-specific transcriptional mechanisms. However, the molecular processes that regulate chromatin domains and thereby dictate transcription of key endothelial genes are poorly understood. Here, we report that, in endothelial cells, angiogenic signal-mediated transcriptional induction of Vegfr1 (vascular endothelial growth factor receptor 1) is dependent on the histone chaperone, HIRA (histone cell cycle regulation-defective homolog A). Our molecular analyses revealed that, in response to angiogenic signals, HIRA is induced in endothelial cells and mediates incorporation of lysine 56 acetylated histone H3.3 (H3acK56) at the chromatin domain of Vegfr1. HIRA-mediated incorporation of H3acK56 is a general mechanism associated with transcriptional induction of several angiogenic genes in endothelial cells. Depletion of HIRA inhibits H3acK56 incorporation and transcriptional induction of Vegfr1 and other angiogenic genes. Our functional analyses revealed that depletion of HIRA abrogates endothelial network formation on Matrigel and inhibits angiogenesis in an in vivo Matrigel plug assay. Furthermore, analysis in a laser-induced choroidal neovascularization model showed that depletion of HIRA significantly inhibits neovascularization. Our results for the first time decipher a histone chaperone (HIRA)-dependent molecular mechanism in endothelial gene regulation and indicate that histone chaperones could be new targets for angiogenesis therapy.
Department of Pathology and Laboratory Medicine, Division of Cancer and Developmental Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Debasree
D
Dutta
Soma
S
Ray
Pratik
P
Home
Biswarup
B
Saha
Shoujian
S
Wang
Nader
N
Sheibani
Osama
O
Tawfik
Niki
N
Cheng
Soumen
S
Paul
D000818:Animals; D002843:Chromatin / Q000737:chemistry*; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000737:chemistry*; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008239:Lysine / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000737:chemistry; D009389:Neovascularization, Pathologic; D011509:Proteoglycans / Q000737:chemistry; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry
D002843:Chromatin; D004338:Drug Combinations; D006657:Histones; D007797:Laminin; D018832:Molecular Chaperones; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D040281:Vascular Endothelial Growth Factor Receptor-1; D008239:Lysine