Shao Ruiqi, Suzuki Takayoshi, Suyama Mikita, Tsukada Yuichi
Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan.
SANKEN, Osaka University, 8-1 Mihogaoka, 567-0047, Ibaraki, Osaka, Japan.
BMC Genomics. 2024 Feb 5;25(1):143. doi: 10.1186/s12864-024-10029-3.
Histone acetylation, which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a crucial role in the control of gene expression. HDAC inhibitors (HDACi) have shown potential in cancer therapy; however, the specific roles of HDACs in early embryos remain unclear. Moreover, although some pan-HDACi have been used to maintain cellular undifferentiated states in early embryos, the specific mechanisms underlying their effects remain unknown. Thus, there remains a significant knowledge gap regarding the application of selective HDACi in early embryos.
To address this gap, we treated early embryos with two selective HDACi (MGCD0103 and T247). Subsequently, we collected and analyzed their transcriptome data at different developmental stages. Our findings unveiled a significant effect of HDACi treatment during the crucial 2-cell stage of zygotes, leading to a delay in embryonic development after T247 and an arrest at 2-cell stage after MGCD0103 administration. Furthermore, we elucidated the regulatory targets underlying this arrested embryonic development, which pinpointed the G2/M phase as the potential period of embryonic development arrest caused by MGCD0103. Moreover, our investigation provided a comprehensive profile of the biological processes that are affected by HDACi, with their main effects being predominantly localized in four aspects of zygotic gene activation (ZGA): RNA splicing, cell cycle regulation, autophagy, and transcription factor regulation. By exploring the transcriptional regulation and epigenetic features of the genes affected by HDACi, we made inferences regarding the potential main pathways via which HDACs affect gene expression in early embryos. Notably, Hdac7 exhibited a distinct response, highlighting its potential as a key player in early embryonic development.
Our study conducted a comprehensive analysis of the effects of HDACi on early embryonic development at the transcriptional level. The results demonstrated that HDACi significantly affected ZGA in embryos, elucidated the distinct actions of various selective HDACi, and identified specific biological pathways and mechanisms via which these inhibitors modulated early embryonic development.
组蛋白乙酰化受组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs）调控，在基因表达控制中起关键作用。HDAC抑制剂（HDACi）已在癌症治疗中显示出潜力；然而，HDACs在早期胚胎中的具体作用仍不清楚。此外，尽管一些泛HDACi已被用于维持早期胚胎中的细胞未分化状态，但其作用的具体机制仍未知。因此，关于选择性HDACi在早期胚胎中的应用仍存在重大知识空白。
为填补这一空白，我们用两种选择性HDACi（MGCD0103和T247）处理早期胚胎。随后，我们在不同发育阶段收集并分析了它们的转录组数据。我们的研究结果揭示了HDACi处理在合子关键的2细胞阶段具有显著影响，导致T247处理后胚胎发育延迟，MGCD0103处理后胚胎停滞在2细胞阶段。此外，我们阐明了这种胚胎发育停滞背后的调控靶点，确定G2/M期是MGCD0103导致胚胎发育停滞的潜在时期。此外，我们的研究提供了受HDACi影响的生物学过程的全面概况，其主要影响主要集中在合子基因激活（ZGA）的四个方面：RNA剪接、细胞周期调控、自噬和转录因子调控。通过探索受HDACi影响的基因的转录调控和表观遗传特征，我们推断了HDACs影响早期胚胎基因表达的潜在主要途径。值得注意的是，Hdac7表现出独特的反应，突出了其作为早期胚胎发育关键参与者的潜力。
我们的研究在转录水平上对HDACi对早期胚胎发育的影响进行了全面分析。结果表明，HDACi显著影响胚胎中的ZGA，阐明了各种选择性HDACi的不同作用，并确定了这些抑制剂调节早期胚胎发育的特定生物学途径和机制。
