Transcription factor 21 regulates expression of ERβ and SF-1 via upstream stimulatory factor-2 in endometriotic tissues
Transcription factor 21 regulates expression of ERβ and SF-1 via upstream stimulatory factor-2 in endometriotic tissues
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转录因子 21 通过上游刺激因子 2 调节子宫内膜异位组织中 ERβ 和 SF-1 的表达
DOI：
10.1016/j.bbagrm.2018.06.008
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发表时间：
2018-08-01
影响因子：
4.7
通讯作者：
Xue, Qing
中科院分区：
文献类型：
--
作者：
Wu, Pei-Li;Zhou, Yan;Xue, Qing
子宫内膜异位间质细胞(ESC)高表达类固醇生成因子-1(SF-1)和雌激素受体β(ER-β)，但其调控机制尚不清楚。转录因子21(TCF21)属于螺旋-环-螺旋(BHLH)家族，通过与E-box元件结合来调节基因表达。在此，我们试图确定TCF21对子宫内膜异位症中SF-1和ERβ表达的分子机制。我们发现TCF21在ESCs中的表达高于在子宫内膜间质细胞中的表达，并且与ESCs中SF-1和ERβ的表达呈正相关。由于E-box元件对NR5A1启动子活性的重要性已有报道，我们进行了点突变和荧光素酶分析，揭示了ESR2启动子中的E-box序列也是调节ERβ表达的关键元件。上游刺激因子2(USF2)是另一种参与转录调控的bHLH因子。进一步的分析表明，它不是TCF21，但USF2在ESCs中与NR5A1和ESR2启动子的结合亲和力高于在EMS中。此外，TCF21基因敲除通过破坏TCF21-USF2复合体显著降低了USF2与NR5A1和ESR2启动子的结合活性。同时，调控TCF21的表达显著影响MMP9和CyclinD1的表达，并影响ESCs的增殖和侵袭能力。此外，TCF21在异位内膜移植物中的缺失降低了SF-1和ERβ的表达，消除了小鼠异位病变的生长。总而言之，TCF21在子宫内膜异位症的发病机制中发挥了关键作用，提示了未来治疗的潜在药物靶点。
Steroidogenic factor-1 (SF-1, encoded by NR5A1) and estrogen receptor beta (ER beta, encoded by ESR2), which are highly expressed in endometriotic stromal cells (ESCs), contribute to the pathogenesis of endometriosis, but the regulation mechanism remains largely unknown. Transcription factor 21 (TCF21) belongs to the helix-loop-helix (bHLH) family characterized by regulating gene expression via binding to E-box element. Here, we attempted to determine the molecular mechanism of TCF21 on SF-1 and ER beta expression in endometriosis. We found that TCF21 expression in ESCs was higher than that in endometrial stromal cells (EMs), and positively correlated with SF-1 and ER beta expression in ESCs. Since the importance of E-box element for NR5A1 promoter activity has been previously reported, we performed site-mutation and luciferase assay, revealing that the E-box sequence in the ESR2 promoter is also a critical element modulating ER beta expression. Upstream stimulatory factor 2 (USF2) is another bHLH factor implicated in transcriptional regulation. Further analyses elucidated that it is not TCF21, but USF2 exhibited higher binding affinities in ESCs to NR5A1 and ESR2 promoters than in EMs. Additionally, TCF21 knockdown significantly decreased the binding activities of USF2 to NR5A1 and ESR2 promoters via disruption of the TCF21-USF2 complex. Meanwhile, manipulating TCF21 expression significantly affected MMP9 and cyclinD1 expression, as wells as proliferation and invasion of ESCs. Moreover, TCF21 depletion in endometriotic xenografts reduced SF-1 and ER beta expression, abrogating ectopic lesion growth in mice. Cumulatively, a critical role of TCF21 in the pathogenesis of endometriosis is demonstrated, suggesting a potential druggable target for future therapy.