Study on the role of histone acetylation in the cell growth and differentiation of human endometrium

组蛋白乙酰转移酶和组蛋白脱乙酰酶决定组蛋白的乙酰化状态，调节基因转录。蜕膜化是孕激素诱导雌激素诱导的子宫内膜间质细胞分化，对着床和维持妊娠至关重要。在此，我们发现hDAC的特异性抑制剂曲古抑素A(Tsa)以剂量依赖的方式促进蜕膜化标记物如胰岛素样生长因子结合蛋白-1(IGFBP-1)和催乳素(PRL)的上调，这种上调作用受17β-雌二醇(E_2)和孕酮(P_4)的影响，但不能促进从人子宫内膜腺细胞分离出来的腺细胞。加入TSA后，类似于蜕膜转化的形态变化也得到了增强。酸性尿素Triton凝胶分析和乙酰化组蛋白特异性抗体免疫印迹显示，E2+P4组乙酰化H3和H4水平显著增加，与TSA共同处理后其增加幅度更大。众所周知，单个HAT对特定的位点和底物具有乙酰化偏好。鉴于卵巢类固醇治疗后的乙酰化位点，SRC-1和CBP/p300可能是在蜕膜化过程中负责组蛋白乙酰化的HATS候选基因。染色质免疫沉淀分析显示，E2+P4处理增加了IGFBP-1启动子近端与乙酰化H4相关的孕酮反应区的数量，TSA的共同加入显著增强了该区域的数量。综上所述，我们的结果表明，组蛋白乙酰化与人胚胎干细胞的分化密切相关，而TSA有可能通过促进孕酮的作用而促进蜕膜化。

Histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones, regulating gene transcription. Decidualization is the progestin-induced differentiation of estrogen-primed endometrial stromal cells (ESCs), which is crucial for implantation and maintenance of pregnancy. We here show that trichostatin A (TSA), a specific HDAC inhibitor, enhances the up-regulation of decidualization markers such as insulin-like growth factor binding protein-1 (IGFBP-1) and prolactin in a dose-dependent manner that is directed by 17β-estradiol (E2) plus progesterone (P4) in cultured ESCs, but not glandular cells, both isolated from human endometrium. Morphological changes resembling decidual transformation were also augmented by co-addition of TSA. Acid urea triton gel analysis and immunoblot using acetylated histone type specific antibodies demonstrated that treatment with E2 plus P4 significantly increased the levels of acetylated H3 and H4 whose increment was augmented by cotreatment with TSA. Individual HATs are known to possess acetylation preferences for specific sites and substrates. Given the acetylation sites upon treatment with ovarian steroids as demonstrated in this study, SRC-1 and CBP/p300 may be likely candidates for HATs responsible for histone acetylation in the process of decidualization. Chromatin immunoprecipitation assay revealed that treatment with E2 plus P4 increased the amount of proximal progesterone-responsive region of IGFBP-1 promoter associated with acetylated H4, which was dramatically enhanced by co-addition of TSA. Taken together, our results suggest that histone acetylation is deeply involved in differentiation of human ESCs and that TSA has a potential as an enhancer of decidualization through promotion of progesterone action