Laboratory of Mammalian Molecular Embryology, College of Animal Sciences, Zhejiang University, Hangzhou, China.
Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FASEB J. 2019 Nov;33(11):12541-12553. doi: 10.1096/fj.201901213R. Epub 2019 Aug 26.
Suppressor interacting 3a (Sin3a) is a scaffold component of the chromatin repressive complex Sin3/histone deacetylase (Hdac). Sin3a has been shown as a hub gene driving preimplantation development in both mice and humans. However, its precise functions during preimplantation development remain unclear. Here, we show that the embryos arrested at morula stage upon specific depletion of Sin3a in mouse early embryos. Given the reduced cell number in Sin3a-depleted embryos, blocked cell proliferation is observed, likely because of the increased level of Trp53 acetylation at lysine 379. Moreover, we found that Sin3a depletion reduces Cdx2 and Tir Na Nog (Nanog), suggesting a failure of the first cell fate decision. In addition, we noted a striking increase of genome-wide DNA methylation, likely attributed to the increased nuclear DNA methyltransferase 1 observed in Sin3a-depleted embryos. Notably, RNA sequencing analyses showed 717 genes are differentially expressed, and Gene Ontology analysis of down-regulated genes (, ) revealed top enriched terms involving protein deacetylation. Consistently, we confirmed a significant decrease of Hdac1 mRNA and protein abundance. Importantly, the development and Trp53 acetylation in Sin3a-depleted embryos could be rescued by expression of but not . In summary, our results indicate a vital role of Sin3a in safeguarding the developmental progression through the morula-to-blastocyst transition Hdac1.-Zhao, P., Li, S., Wang, H., Dang, Y., Wang, L., Liu, T., Wang, S., Li, X., Zhang, K. Sin3a regulates the developmental progression through morula-to-blastocyst transition Hdac1.
抑制物相互作用蛋白 3a（Sin3a）是染色质抑制复合物 Sin3/组蛋白脱乙酰酶（Hdac）的支架成分。Sin3a 已被证明是驱动小鼠和人类胚胎着床前发育的枢纽基因。然而，其在胚胎着床前发育中的精确功能仍不清楚。在这里，我们显示在小鼠早期胚胎中特异性耗尽 Sin3a 会导致胚胎停滞在桑葚胚阶段。鉴于 Sin3a 耗尽胚胎中的细胞数量减少，观察到细胞增殖受阻，这可能是由于赖氨酸 379 乙酰化的 Trp53 水平增加所致。此外，我们发现 Sin3a 耗尽会降低 Cdx2 和 Tir Na Nog（Nanog），表明第一次细胞命运决定失败。此外，我们注意到全基因组 DNA 甲基化显著增加，这可能归因于 Sin3a 耗尽胚胎中观察到的核 DNA 甲基转移酶 1 的增加。值得注意的是，RNA 测序分析显示 717 个基因表达差异，下调基因的基因本体论分析（GO:0006954）显示富含与蛋白质去乙酰化相关的术语。一致地，我们证实 Hdac1 mRNA 和蛋白质丰度显著降低。重要的是，Sin3a 耗尽胚胎中的发育和 Trp53 乙酰化可以通过表达 但不是 来挽救。总之，我们的结果表明 Sin3a 在通过桑葚胚到囊胚的过渡来保护发育进展方面起着至关重要的作用。
