首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling
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Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling

机译:组蛋白H3赖氨酸36甲基转移酶Hypb / Setd2是胚胎血管重塑所必需的

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摘要

HYPB is a human histone H3 lysine 36 (H3K36)–specific methyltransferase and acts as the ortholog of yeast Set2. This study explored the physiological function of mammalian HYPB using knockout mice. Homozygous disruption of Hypb impaired H3K36 trimethylation but not mono- or dimethylation, and resulted in embryonic lethality at E10.5-E11.5. Severe vascular defects were observed in the Hypb −/− embryo, yolk sac, and placenta. The abnormally dilated capillaries in mutant embryos and yolk sacs could not be remodeled into large blood vessels or intricate networks, and the aberrantly rounded mesodermal cells exhibited weakened interaction with endothelial cells. The embryonic vessels failed to invade the labyrinthine layer of placenta, which impaired the embryonic–maternal vascular connection. These defects could not be rescued by wild-type tetraploid blastocysts, excluding the possibility that they were caused by the extraembryonic tissues. Consistent with these phenotypes, gene expression profiling in wild-type and Hypb −/− yolk sacs revealed that the Hypb disruption altered the expression of some genes involved in vascular remodeling. At the cellular level, Hypb −/− embryonic stem cell–derived embryonic bodies, as well as in vitro–cultured human endothelial cells with siRNA-mediated suppression of HYPB, showed obvious defects in cell migration and invasion during vessel formation, suggesting an intrinsic role of Hypb in vascular development. Taken together, these results indicate that Hypb is required for embryonic vascular remodeling and provide a tool to study the function of H3K36 methylation in vasculogenesis/angiogenesis.
机译:HYPB是人类组蛋白H3赖氨酸36(H3K36)特异的甲基转移酶,可作为酵母Set2的直系同源物。这项研究使用敲除小鼠探索了哺乳动物HYPB的生理功能。 Hypb的纯合破坏会损害H3K36三甲基化,但不会破坏单或二甲基化,并导致E10.5-E11.5处的胚胎致死性。在Hypb -/-胚胎,卵黄囊和胎盘中观察到严重的血管缺陷。突变胚和卵黄囊中异常扩张的毛细血管无法重塑成大血管或复杂的网络,异常圆形的中胚层细胞与内皮细胞的相互作用减弱。胚胎血管未能侵入胎盘的迷宫层,从而损害了胚胎与母体的血管连接。这些缺陷不能通过野生型四倍体胚泡得以挽救,除了它们是由胚外组织引起的可能性之外。与这些表型一致,野生型和Hypb -/-卵黄囊中的基因表达谱显示,Hypb破坏改变了一些参与血管重塑的基因的表达。在细胞水平上,Hypb -/-胚胎干细胞衍生的胚体以及具有siRNA介导的HYPB抑制作用的体外培养人内皮细胞在细胞迁移和侵袭中均表现出明显的缺陷。在血管形成过程中,提示Hypb在血管发育中具有内在作用。综上所述,这些结果表明Hypb是胚胎血管重塑所必需的,并提供了研究H3K36甲基化在血管生成/血管生成中功能的工具。

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