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首页> 外文期刊>Molecular and Cellular Biology >A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation
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A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation

机译：缺少1和人类绒毛膜促性腺激素（hCG）的胶质细胞之间的正反馈回路调节胎盘hCGβ的表达和细胞分化。

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Human chorionic gonadotropin (hCG) is composed of a common α subunit and a placenta-specific β subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cyclic AMP (cAMP). Although the ubiquitous activating protein 2 (AP2) transcription factors TFAP2A and TFAP2C may regulate hCGβ expression, it remains unclear how cAMP stimulates placenta-specific hCGβ gene expression and trophoblastic differentiation. Here we demonstrated that the placental transcription factor glial cells missing 1 (GCM1) binds to a highly conserved promoter region in all six hCGβ paralogues by chromatin immunoprecipitation-on-chip (ChIP-chip) analyses. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate the hCGβ promoter through a GCM1-binding site (GBS1), which also constitutes a previously identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between the hCGβ promoter and GCM1 but not TFAP2C. Indeed, the hCG-cAMP-protein kinase A (PKA) signaling pathway also stimulates Ser269 and Ser275 phosphorylation of GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the fusogenic protein syncytin-1, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCGβ expression and cell differentiation.
机译：人绒毛膜促性腺激素（hCG）由一个常见的α亚基和一个胎盘特异性β亚基组成。重要的是，hCG在分化和多核合体滋养层细胞中高表达，它是通过滋养层细胞融合形成并受环AMP（cAMP）刺激的。尽管普遍存在的活化蛋白2（AP2）转录因子TFAP2A和TFAP2C可以调节hCGβ的表达，但仍不清楚cAMP如何刺激胎盘特异性hCGβ基因的表达和滋养细胞分化。在这里，我们通过芯片上的染色质免疫沉淀（ChIP-chip）分析证明，缺失的胎盘转录因子神经胶质细胞（GCM1）与所有六个hCGβ旁系同源物的高度保守的启动子区域结合。我们进一步表明，cAMP刺激GCM1和CBP共激活因子通过GCM1结合位点（GBS1）激活hCGβ启动子，该位点也构成了先前确定的AP2位点。鉴于TFAP2C可能与GCM1竞争GBS1，因此cAMP增强了hCGβ启动子和GCM1之间的关联，但不增强TFAP2C。实际上，hCG-cAMP-蛋白激酶A（PKA）信号传导途径还刺激了GCM1的Ser269和Ser275磷酸化，从而募集了CBP来介导GCM1的乙酰化和稳定作用。因此，hCG刺激GCM1靶基因（包括融合蛋白syncytin-1）的表达，从而促进胎盘细胞融合。我们的研究揭示了GCM1和hCG之间的正反馈回路调节胎盘hCGβ表达和细胞分化。

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