Estrogen-Related Receptor γ (ERRγ) Mediates Oxygen-Dependent Induction of Aromatase (CYP19) Gene Expression during Human Trophoblast Differentiation
Estrogen-Related Receptor γ (ERRγ) Mediates Oxygen-Dependent Induction of Aromatase (CYP19) Gene Expression during Human Trophoblast Differentiation
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DOI：
10.1210/me.2011-1012
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发表时间：
2011-09-01
影响因子：
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通讯作者：
Mendelson, Carole R.
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文献类型：
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作者：
Kumar, Premlata;Mendelson, Carole R.
人细胞滋养层细胞分化为合体滋养层细胞和相关的芳香酶/hCYP19基因表达的诱导依赖于关键的O(2)张力；然而，潜在的分子机制仍不清楚。在这项研究中，我们提供了令人信服的证据，证明孤儿核受体雌激素相关受体伽马(ERR伽马)的表达也是O2依赖的，在人类合体滋养层细胞分化过程中被诱导，并在胎盘特异性hCYP19I的诱导中发挥强制性作用。1基因表达。用选择性ERRγ激动剂DY131治疗或过度表达ERRγ，可刺激合体滋养层细胞hCYP19的表达。ERR-γ的过表达可阻止低氧抑制培养滋养层细胞hCYP19基因的表达。相反，小干扰RNA介导的原代滋养层细胞内源性ERR-γ基因敲除显著抑制hCYP19的表达。在转基因胎盘细胞中的启动子和定点突变研究发现，胎盘特异性hCYP19启动子I.1中存在一个核受体元件，这是ERR伽马刺激活性所必需的。通过染色质免疫沉淀评估，在滋养层细胞分化过程中，内源性ERR-γ在hCYP19启动子的核受体元件区域的募集被低氧所阻止。去铁胺诱导的低氧诱导因子-1α(HIF-1α)水平降低ERR-γ的表达，而内源性HIF-1α的敲除可阻止缺氧对ERR-γ的抑制。对低氧培养的滋养层细胞的染色质免疫沉淀分析显示，HIF-1α募集到ERRγ启动子中两个假定的缺氧反应元件之一，为HIF-1α直接参与ERRγ表达提供了体内证据。综上所述，这些新的发现确认Err Gamma是一种O(2)依赖的转录因子和HIF-1α靶基因，在人类滋养层细胞分化过程中，HIF-1α在诱导hCYP19表达方面发挥了关键作用。(分子内分泌学25：1513-1526,2011)
Differentiation of human cytotrophoblasts to syncytiotrophoblast and the associated induction of aromatase/hCYP19 gene expression are dependent upon a critical O(2) tension; however, the underlying molecular mechanisms remain undefined. In this study, we provide compelling evidence that expression of the orphan nuclear receptor, estrogen-related receptor gamma (ERR gamma), is also O2 dependent, induced during human syncytiotrophoblast differentiation, and plays an obligatory role in the induction of placenta-specific hCYP19I. 1 gene expression. Treatment with the selective ERR gamma agonist, DY131, or overexpression of ERR gamma, stimulated hCYP19 expression in syncytiotrophoblast. Overexpression of ERR gamma prevented effects of hypoxia to repress hCYP19 gene expression in cultured trophoblasts. Conversely, small interfering RNA-mediated knockdown of endogenous ERR gamma in primary trophoblasts markedly inhibited hCYP19 expression. Promoter and site-directed mutagenesis studies in transfected placental cells identified a nuclear receptor element within placenta-specific hCYP19 promoter I. 1 required for ERR gamma-stimulated activity. Recruitment of endogenous ERR gamma to the nuclear receptor element region in hCYP19 promoter during trophoblast differentiation, assessed by chromatin immunoprecipitation, was prevented by hypoxia. Deferoxamine-induced hypoxia-inducible factor-1 alpha (HIF-1 alpha) levels decreased ERR gamma expression, whereas knockdown of endogenous HIF-1 alpha prevented ERR gamma suppression by hypoxia. Chromatin immunoprecipitation analysis of trophoblasts cultured in hypoxia revealed recruitment of HIF-1 alpha to one of two putative hypoxia response elements in the ERR gamma promoter, providing in vivo evidence of a direct HIF-1 alpha involvement in ERR gamma expression. Collectively, these novel findings identify ERR gamma as an O(2)-dependent transcription factor and HIF-1 alpha target gene that serves a critical role in the induction of hCYP19 expression during human trophoblast differentiation. (Molecular Endocrinology 25: 1513-1526, 2011)