Lv Weiying, Guo Xudong, Wang Guiying, Xu Yanxin, Kang Jiuhong
Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, P.R. China.
PLoS One. 2014 Nov 20;9(11):e113262. doi: 10.1371/journal.pone.0113262. eCollection 2014.
The important role of histone acetylation alteration has become increasingly recognized in mesodermal lineage differentiation and development. However, the contribution of individual histone deacetylases (HDACs) to mesoderm specification remains poorly understood. In this report, we found that trichostatin A (TSA), an inhibitor of histone deacetylase (HDACi), could induce early differentiation of embryonic stem cells (ESCs) and promote mesodermal lineage differentiation. Further analysis showed that the expression levels of HDAC1 and 3 are decreased gradually during ESCs differentiation. Ectopic expression of HDAC1 or 3 significantly inhibited differentiation into the mesodermal lineage. By contrast, loss of either HDAC1 or 3 enhanced the mesodermal differentiation of ESCs. Additionally, we demonstrated that the activity of HDAC1 and 3 is indeed required for the regulation of mesoderm gene expression. Furthermore, HDAC1 and 3 were found to interact physically with the T-box transcription factor T/Bry, which is critical for mesodermal lineage commitment. These findings indicate a key mechanism for the specific role of HDAC1 and 3 in mammalian mesoderm specification.
组蛋白乙酰化改变在中胚层谱系分化和发育中的重要作用已越来越受到认可。然而，单个组蛋白去乙酰化酶（HDACs）对中胚层特化的贡献仍知之甚少。在本报告中，我们发现曲古抑菌素A（TSA），一种组蛋白去乙酰化酶抑制剂（HDACi），可以诱导胚胎干细胞（ESCs）的早期分化并促进中胚层谱系分化。进一步分析表明，在ESCs分化过程中，HDAC1和3的表达水平逐渐降低。HDAC1或3的异位表达显著抑制向中胚层谱系的分化。相比之下，HDAC1或3的缺失增强了ESCs的中胚层分化。此外，我们证明HDAC1和3的活性确实是调节中胚层基因表达所必需的。此外，发现HDAC1和3与T盒转录因子T/Bry发生物理相互作用，T/Bry对中胚层谱系定向分化至关重要。这些发现揭示了HDAC1和3在哺乳动物中胚层特化中发挥特定作用的关键机制。
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