1. Endothelial-specific YY1 governs sprouting angiogenesis through directly interacting with RBPJ
- Author
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Meimei Yin, Huan Liu, Jia Guo, Xiuying Pei, Shuya Zhang, Marina Koroleva, Ji Young Kim, Zheng Gen Jin, and Suowen Xu
- Subjects
Male ,Angiogenesis ,Notch signaling pathway ,Neovascularization, Physiologic ,Mice ,Morphogenesis ,Animals ,Humans ,Transcription factor ,YY1 Transcription Factor ,Sprouting angiogenesis ,Mice, Knockout ,Multidisciplinary ,Neovascularization, Pathologic ,Receptors, Notch ,Chemistry ,YY1 ,RBPJ ,Endothelial Cells ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,Retinal Vessels ,Cell Differentiation ,Biological Sciences ,Cell biology ,Endothelial stem cell ,Mice, Inbred C57BL ,Notch proteins ,Immunoglobulin J Recombination Signal Sequence-Binding Protein ,embryonic structures ,Female ,Carrier Proteins ,Protein Binding ,Signal Transduction ,Transcription Factors - 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(iΔEC)) mice exhibited a scarcity of retinal sprouting angiogenesis with fewer endothelial tip cells. YY1(iΔEC) 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.
- Published
- 2020