Thymopentin alleviates premature ovarian failure in mice by activating YY2/Lin28A and inhibiting the expression of let-7 family microRNAs.
Thymopentin alleviates premature ovarian failure in mice by activating YY2/Lin28A and inhibiting the expression of let-7 family microRNAs.
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DOI：
10.1111/cpr.13089
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发表时间：
2021-08
影响因子：
8.5
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Liu T;Jing F;Huang P;Geng Z;Xu J;Li J;Chen D;Zhu Y;Wang Z;Huang W;Chen C
胸腺五肽（5 TP）显著改善了由高脂高糖（HFHS）饮食诱导的典型小鼠卵巢早衰（POF）症状。然而，其效果和机制仍不清楚。采用RNA-Seq技术检测各组间差异表达基因。制备HFHS诱导的POF小鼠模型，并使用聚（乳酸-共-乙醇酸）（PLGA）作为载体注射siRNA。RNA-Seq结果显示，5 TP促进了HFHS-POF小鼠卵巢颗粒细胞（mOGC）中阴阳2（YY 2）的表达。荧光素酶报告基因分析表明，5 TP可促进YY 2与Lin 28 A启动子上的特异性序列C（C/T）AT（G/C）（G/T）结合，从而促进Lin 28 A的转录和表达。我们将靶向YY 2的PLGA交联siRNA纳米颗粒连续注射到HFHS-POF小鼠（siYY2@PLGA）中，这显著降低了5 TP的治疗效果。siYY2@PLGA注射还显著减弱了5 TP诱导的mOGC中Lin 28 a表达的上调，并增强了let-7家族microRNA的表达，从而抑制了mOGC的增殖和分裂。qPCR结果显示，POF患者和正常女性之间的外泌体衍生的Yy 2 mRNA表达水平存在显著差异，并且外泌体衍生的Yy 2表达水平与血液激素炔雌醇、孕酮和雌二醇的外周浓度之间存在特异性相关性。胸腺五肽通过刺激转录因子YY 2的表达，促进Lin 28 A的转录激活，抑制let-7家族microRNA的活性，延缓卵巢颗粒细胞的衰老，最终达到治疗小鼠POF的效果。胸腺五肽通过刺激转录因子YY 2的表达，促进Lin 28 A的转录激活，抑制let-7家族microRNA的活性，从而减轻卵巢颗粒细胞的衰老，最终达到治疗小鼠POF的作用。
Thymopentin (5TP) significantly improved typical murine premature ovarian failure (POF) symptoms induced by a high‐fat and high‐sugar (HFHS) diet. However, its effect and mechanism remain unclear. RNA‐Seq was used to detect the differentially expressed genes among each group. HFHS‐induced POF mouse model was generated and injected with siRNA using Poly (lactic‐co‐glycolic acid) (PLGA) as a carrier. RNA‐Seq suggested that 5TP promoted the expression of Yin Yang 2 (YY2) in mouse ovarian granulosa cell (mOGC) of HFHS‐POF mice. Luciferase reporter assay indicated that 5TP promoted the binding of YY2 to the specific sequence C(C/T)AT(G/C)(G/T) on the Lin28A promoter and promoted Lin28A transcription and expression. We continuously injected PLGA‐cross‐linked siRNA nanoparticles targeting YY2 into HFHS‐POF mice (siYY2@PLGA), which significantly reduced the therapeutic effect of 5TP. siYY2@PLGA injection also significantly attenuated the upregulation of Lin28a expression in mOGCs induced by 5TP and enhanced the expression of let‐7 family microRNAs, thereby inhibiting the proliferation and division of mOGCs. qPCR results showed that there was a significant difference in the expression levels of exosome‐derived Yy2 mRNAs between POF patients and normal women, and that there was a specific correlation between the expression level of exosome‐derived Yy2 and the peripheral concentrations of the blood hormones pregnenolone, progesterone and oestradiol. Thymopentin promotes the transcriptional activation of Lin28A via stimulating transcription factor YY2 expression, inhibits the activity of let‐7 family microRNAs and alleviates the ageing of ovarian granulosa cells, ultimately achieving a therapeutic effect on POF in mice. Thymopentin promotes the transcriptional activation of Lin28A via stimulating transcription factor YY2 expression, inhibit the activity of let‐7 family microRNAs, and alleviate the aging of ovarian granulosa cells, ultimately achieving a therapeutic effect on POF in mice.
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