The nuclear receptor REV-ERBα represses the transcription of growth/differentiation factor 10 and 15 genes in rat endometrium stromal cells.
The nuclear receptor REV-ERBα represses the transcription of growth/differentiation factor 10 and 15 genes in rat endometrium stromal cells.
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DOI：
10.14814/phy2.12663
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发表时间：
2016-02
影响因子：
2.5
通讯作者：
Hattori MA
中科院分区：
文献类型：
--
作者：
Zhao L;Isayama K;Chen H;Yamauchi N;Shigeyoshi Y;Hashimoto S;Hattori MA
子宫中的细胞振荡器通过将时钟蛋白夹带至许多下游基因（包括生长/分化因子 (Gdf)10 和 Gdf15），在哺乳动物的妊娠过程中发挥关键作用。在子宫蜕膜化过程中，Gdf10和Gdf15的表达显着增加，但子宫中Gdf基因表达调控的机制尚不清楚。在这里，我们通过使用从妊娠 Per2-dLuc 转基因大鼠中分离的子宫内膜基质细胞（UESC），重点研究了细胞振荡器在 Gdf 家族表达中的功能。在体外蜕膜化的 UESC 中，Per2-dLuc 生物发光活性显着下降，同时规范时钟基因的表达下调。相反，Gdf的Gdf10和Gdf15的表达上调。在用 Bmal1 特异性 siRNA 转染的 UESC 中，Rev-erbα 表达下调，Gdf10 和 Gdf15 表达上调。然而，Gdf5、Gdf7 和 Gdf11 并未受到 Bmal1 沉默的显着影响。在存在或不存在孕酮的情况下，用 REV-ERB α 拮抗剂治疗后，Gdf10 和 Gdf15 的表达增强。染色质免疫沉淀-PCR 分析揭示了 REV-ERB α 通过识别 UESC 基因启动子对 Gdf10 和 Gdf15 表达的抑制作用。总的来说，我们的研究结果表明，REV-ERB α 的减弱会导致蜕膜细胞中 Gdf10 和 Gdf15 的上调，从而导致细胞振荡器受损。我们的结果提供了关于细胞振荡器在 UESC 分化过程中调节下游基因表达的功能的新证据。
Cellular oscillators in the uterus play critical roles in the gestation processes of mammals through entraining of the clock proteins to numerous downstream genes, including growth/differentiation factor (Gdf)10 and Gdf15. The expression of Gdf10 and Gdf15 is significantly increased in the uterus during decidualization, but the mechanism underlying the regulation of Gdf gene expression in the uterus is poorly understood. Here, we focused on the function of the cellular oscillators in the expression of Gdf family by using uterine endometrial stromal cells (UESCs) isolated from pregnant Per2‐dLuc transgenic rats. A significant decline of Per2‐dLuc bioluminescence activity was induced in in vitro decidualized UESCs, and concomitantly the expression of canonical clock genes was downregulated. Conversely, the expression of Gdf10 and Gdf15 of the Gdf was upregulated. In UESCs transfected with Bmal1‐specific siRNA, in which Rev‐erbα expression was downregulated, Gdf10 and Gdf15 were upregulated. However, Gdf5, Gdf7, and Gdf11 were not significantly affected by Bmal1 silencing. The expression of Gdf10 and Gdf15 was enhanced after treatment with a REV‐ERB α antagonist in the presence or absence of progesterone. Chromatin immunoprecipitation‐PCR analysis revealed the inhibitory effect of REV‐ERB α on the expression of Gdf10 and Gdf15 in UESCs by recognizing their gene promoters. Collectively, our findings indicate that the attenuation of REV‐ERB α leads to an upregulation of Gdf10 and Gdf15 in decidual cells, in which cellular oscillators are impaired. Our results provide novel evidence regarding the functions of cellular oscillators regulating the expression of downstream genes during the differentiation of UESCs.