Department of Cardiology, Huaihe Hospital of Henan University, Kaifeng, Henan Province, China.
School of Medicine, Hunan Normal University, Changsha, Hunan, China.
PLoS One. 2021 Apr 21;16(4):e0250267. doi: 10.1371/journal.pone.0250267. eCollection 2021.
4-phenylbutyrate (4-PBA), a terminal aromatic substituted fatty acid, is used widely to specifically attenuate endoplasmic reticulum (ER) stress and inhibit histone deacetylases (HDACs). In this study, we investigated the effect of 4-PBA on cardiac differentiation of mouse embryonic stem (ES) cells. Herein, we found that 4-PBA regulated cardiac differentiation in a stage-specific manner just like trichostatin A (TSA), a well-known HDAC inhibitor. 4-PBA and TSA favored the early-stage differentiation, but inhibited the late-stage cardiac differentiation via acetylation. Mechanistic studies suggested that HDACs exhibited a temporal expression profiling during cardiomyogenesis. Hdac1 expression underwent a decrease at the early stage, while was upregulated at the late stage of cardiac induction. During the early stage of cardiac differentiation, acetylation favored the induction of Isl1 and Nkx2.5, two transcription factors of cardiac progenitors. During the late stage, histone acetylation induced by 4-PBA or TSA interrupted the gene silence of Oct4, a key determinant of self-renewal and pluripotency. Thereby, 4-PBA and TSA at the late stage hindered the exit from pluripotency, and attenuated the expression of cardiac-specific contractile proteins. Overexpression of HDAC1 and p300 exerted different effects at the distinct stages of cardiac induction. Collectively, our study shows that timely manipulation of HDACs exhibits distinct effects on cardiac differentiation. And the context-dependent effects of HDAC inhibitors depend on cell differentiation states marked by the temporal expression of pluripotency-associated genes.
4-苯丁酸（4-PBA）是一种末端芳香取代脂肪酸，广泛用于特异性减弱内质网（ER）应激和抑制组蛋白去乙酰化酶（HDACs）。在这项研究中，我们研究了 4-PBA 对小鼠胚胎干细胞（ES）心脏分化的影响。在此，我们发现 4-PBA 像众所周知的 HDAC 抑制剂曲古抑菌素 A（TSA）一样，以阶段特异性方式调节心脏分化。4-PBA 和 TSA 有利于早期分化，但通过乙酰化抑制晚期心脏分化。机制研究表明，HDACs 在心肌发生过程中表现出时间表达谱。Hdac1 的表达在早期阶段下降，而在心脏诱导的晚期阶段上调。在心脏分化的早期阶段，乙酰化有利于诱导心脏祖细胞的转录因子 Isl1 和 Nkx2.5。在晚期，4-PBA 或 TSA 诱导的组蛋白乙酰化中断了多能性和自我更新的关键决定因素 Oct4 的基因沉默。因此，4-PBA 和 TSA 在晚期阻碍了多能性的退出，并减弱了心脏特异性收缩蛋白的表达。HDAC1 和 p300 的过表达在心脏诱导的不同阶段具有不同的作用。总之，我们的研究表明，HDAC 的适时操作对心脏分化具有不同的影响。并且 HDAC 抑制剂的上下文相关效应取决于多能性相关基因的时间表达标记的细胞分化状态。
