Endothelial-specific YY1 governs sprouting angiogenesis through directly interacting with RBPJ
Endothelial-specific YY1 governs sprouting angiogenesis through directly interacting with RBPJ
复制标题
内皮特异性 YY1 通过直接与 RBPJ 相互作用来控制萌芽血管生成
DOI：
10.1073/pnas.1916198117
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发表时间：
2020-03-03
影响因子：
11.1
通讯作者：
Jin, Zheng Gen
中科院分区：
文献类型：
--
作者：
Zhang, Shuya;Kim, Ji Young;Jin, Zheng Gen
意义内皮发芽对于生理性和病理性血管生成都是至关重要的。然而，精确调控内皮发芽的分子机制尚未完全了解。在这里，我们表明，转录因子Yin Ying 1（YY 1）的功能作为一个阻遏物的Notch信号，通过其抑制的细胞内结构域的Notch蛋白/主谋样蛋白1/重组信号结合蛋白的IG Kappa J区域复合物的形成和调节内皮细胞的tip-stalk命运的决定。我们的研究结果表明，YY 1在调节内皮发芽和血管生成中起着重要作用，并建议YY 1可能是血管生成相关疾病的潜在分子靶点。血管生成，即新血管的形成，受到基因转录程序的严格调控。Yin Ying 1（YY 1）是一种广泛分布的转录因子，具有复杂多样的生物学功能，但YY 1在血管发育和血管生成中的细胞类型特异性作用却知之甚少。在这里，我们报告说，内皮细胞（EC）特异性YY 1基因缺失小鼠导致胚胎死亡的结果异常血管生成和血管缺陷。他莫昔芬诱导的EC特异性YY 1基因敲除（YY 1 i ΔEC）小鼠表现出视网膜出芽血管生成稀少，内皮尖端细胞较少。YY 1 i ΔEC小鼠也表现出严重的视网膜血管成熟障碍。在离体小鼠主动脉环测定和人EC培养系统中，YY 1耗竭损害内皮发芽和迁移。从机制上讲，YY 1作为Notch信号传导的阻遏蛋白发挥作用，控制EC尖-茎命运决定。YY 1缺陷增强Notch依赖基因的表达，减少尖端细胞的形成。具体而言，YY 1结合RBPJ（IG Kappa J区的重组信号结合蛋白）的N末端结构域，并与Notch辅激活因子MAML 1（主谋样蛋白1）竞争结合RBPJ，从而损害NICD（Notch蛋白的胞内结构域）/MAML 1/RBPJ复合物的形成。我们的研究揭示了内皮细胞YY 1通过直接与RBPJ相互作用并形成YY 1-RBPJ核抑制复合物在控制出芽血管生成中的重要作用。
Significance Endothelial sprouting is critical for both physiological and pathological angiogenesis. However, the molecular mechanisms underlying precise regulation of endothelial sprouting have not been fully understood. Here we show that the transcription factor Yin Ying 1 (YY1) functions as a repressor of Notch signaling through its inhibition of the intracellular domain of the Notch protein/mastermind-like protein 1/recombination signal binding protein for Ig Kappa J region complex formation and modulates endothelial cell tip-stalk fate determination. Our results reveal that YY1 plays an important role in regulating endothelial sprouting and angiogenesis and suggest YY1 could be a potential molecular target for angiogenesis-related diseases. 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 (YY1iΔEC) mice exhibited a scarcity of retinal sprouting angiogenesis with fewer endothelial tip cells. YY1iΔEC 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.