4-phenylbutyrate exerts stage-specific effects on cardiac differentiation via HDAC inhibition.
4-phenylbutyrate exerts stage-specific effects on cardiac differentiation via HDAC inhibition.
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4-苯基丁酸通过 HDAC 抑制对心脏分化产生阶段特异性影响。
DOI：
10.1371/journal.pone.0250267
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Li T
中科院分区：
文献类型：
--
作者：
Li Y;Weng X;Wang P;He Z;Cheng S;Wang D;Li X;Cheng G;Li T
4-丁酸苯酯（4-PBA）是一种末端芳香族取代脂肪酸，广泛用于特异性减轻内质网（ER）应激和抑制组蛋白脱乙酰酶（HDAC）。本研究探讨了4-PBA对小鼠胚胎干细胞心肌分化的影响。在此，我们发现4-PBA以阶段特异性的方式调节心脏分化，就像众所周知的HDAC抑制剂阿司他丁A（TSA）一样。4-PBA和TSA通过乙酰化作用促进心肌细胞早期分化，但抑制晚期心肌细胞分化。机制研究表明，HDACs在心肌发生过程中表现出时间表达谱。hdac 1表达在诱导早期下降，而在诱导晚期上调。在心脏分化的早期阶段，乙酰化有利于诱导Isl 1和Nkx2.5，心脏祖细胞的两个转录因子。在晚期，由4-PBA或TSA诱导的组蛋白乙酰化中断了Oct 4的基因沉默，Oct 4是自我更新和多能性的关键决定因素。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。HDAC 1和p300的过表达在心脏诱导的不同阶段产生不同的影响。总的来说，我们的研究表明，及时操纵HDAC对心脏分化表现出明显的影响。HDAC抑制剂的环境依赖性效应取决于以多能性相关基因的时间表达为标志的细胞分化状态。
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.
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影响因子：
5.2
作者：
Hoxha, Eneda;Lambers, Erin;Xie, Hehuang;De Andrade, Alexandre;Krishnamurthy, Prasanna;Wasserstrom, John A.;Ramirez, Veronica;Thal, Melissa;Verma, Suresh K.;Soares, Marcelo B.;Kishore, Raj
通讯作者：
Kishore, Raj
影响因子：
5.6
作者：
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通讯作者：
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影响因子：
37.8
作者：
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通讯作者：
Lee, RT
DOI：
10.1073/pnas.0605768103
发表时间：
2006-12-26
影响因子：
11.1
作者：
Naito, Atsuhiko T.;Shiojima, Ichiro;Komuro, Issei
通讯作者：
Komuro, Issei
影响因子：
4
作者：
Karamboulas, Christina;Swedani, Albert;Skerjanc, Ilona S.
通讯作者：
Skerjanc, Ilona S.