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Endothelial-specific YY1 governs sprouting angiogenesis through directly interacting with RBPJ.


ABSTRACT: Angiogenesis, the formation of new blood vessels, is tightly regulated by gene transcriptional programs. Yin Ying 1 (YY1) is a ubiquitously distributed transcription factor with diverse and complex biological functions; however, little is known about the cell-type-specific role of YY1 in vascular development and angiogenesis. Here we report that endothelial cell (EC)-specific YY1 deletion in mice led to embryonic lethality as a result of abnormal angiogenesis and vascular defects. Tamoxifen-inducible EC-specific YY1 knockout (YY1 i?EC ) mice exhibited a scarcity of retinal sprouting angiogenesis with fewer endothelial tip cells. YY1 i?EC mice also displayed severe impairment of retinal vessel maturation. In an ex vivo mouse aortic ring assay and a human EC culture system, YY1 depletion impaired endothelial sprouting and migration. Mechanistically, YY1 functions as a repressor protein of Notch signaling that controls EC tip-stalk fate determination. YY1 deficiency enhanced Notch-dependent gene expression and reduced tip cell formation. Specifically, YY1 bound to the N-terminal domain of RBPJ (recombination signal binding protein for Ig Kappa J region) and competed with the Notch coactivator MAML1 (mastermind-like protein 1) for binding to RBPJ, thereby impairing the NICD (intracellular domain of the Notch protein)/MAML1/RBPJ complex formation. Our study reveals an essential role of endothelial YY1 in controlling sprouting angiogenesis through directly interacting with RBPJ and forming a YY1-RBPJ nuclear repression complex.

SUBMITTER: Zhang S 

PROVIDER: S-EPMC7060702 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Endothelial-specific YY1 governs sprouting angiogenesis through directly interacting with RBPJ.

Zhang Shuya S   Kim Ji Young JY   Xu Suowen S   Liu Huan H   Yin Meimei M   Koroleva Marina M   Guo Jia J   Pei Xiuying X   Jin Zheng Gen ZG  

Proceedings of the National Academy of Sciences of the United States of America 20200219 9


Angiogenesis, the formation of new blood vessels, is tightly regulated by gene transcriptional programs. Yin Ying 1 (YY1) is a ubiquitously distributed transcription factor with diverse and complex biological functions; however, little is known about the cell-type-specific role of YY1 in vascular development and angiogenesis. Here we report that endothelial cell (EC)-specific <i>YY1</i> deletion in mice led to embryonic lethality as a result of abnormal angiogenesis and vascular defects. Tamoxif  ...[more]

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