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Nature子刊:厦大王海滨教授研究组揭示表观遗传调节分子PR-Set7调控子宫腺体发育新机制

摘要 : 2017年7月21日,国际学术权威刊物自然出版集团旗下子刊《Cell Death & Differentiation》杂志在线发表了厦门大学医学院王海滨教授带领的生殖调控研究团队题为 “PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice”的研究论文

2017年7月21日,国际学术权威刊物自然出版集团旗下子刊《Cell Death & Differentiation》杂志在线发表了厦门大学医学院王海滨教授带领的生殖调控研究团队题为 “PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice”的研究论文,研究论文揭示了表观遗传调节分子PR-Set7调控子宫腺体发育的新机制。

子宫是生命孕育的场所,是胎儿发育所必需的器官。子宫腺体是子宫中上皮的特化结构,能分泌各类营养物质和信号分子,对妊娠的建立和维持起着至关重要的作用,子宫腺体发育不良和功能的缺陷常会导致不孕。子宫腺体的发育是一个受到严格调控的过程,其中涉及的机制非常复杂,许多关键环节还有待认识,特别是表观遗传机制对子宫腺体的调控还有待于进一步研究。

王海滨教授带领的生殖调控研究团队利用转基因模式动物研究发现,在小鼠中,子宫上皮细胞的数量需要通过增殖达到一定的阈值才能开始腺体的发生过程,而表观遗传分子PR-Set7的缺失使子宫上皮细胞数量不能达到这一阈值,从而导致腺体发生的失败和不孕。进一步的机制研究发现,PR-Set7的缺失降低了组蛋白相关修饰H4K20me1/2的水平,使DNA损伤修复的关键因子53BP1不能被招募到DNA损伤位点,导致上皮细胞中DNA损伤的持续积累和细胞凋亡,从而使增殖中的上皮细胞数量不能达到腺体发生的阈值,导致腺体发生的失败。另外,本研究又进一步利用了DTA小鼠模型和小鼠出生后注射孕酮模型验证了子宫腺体发生过程中“上皮细胞数量增长阈值”的存在。该研究首次提出了子宫腺体发生过程中“上皮细胞数量增长阈值”学说(见下图),为腺体发生的研究提供了新的切入点。

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子宫腺体发生的“上皮细胞数量增长阈值”模型

原文链接:

PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice

原文摘要:

Formation of secretary endometrial glands in the uterus known as adenogenesis is a typical process of branching morphogenesis involving dynamic epithelial growth and differentiation. Unsuccessful adenogenesis often leads to female infertility. However, it remains largely unexplored so far regarding the epigenetic machinery governing normal endometrial gland formation. Here, we demonstrated that PR-Set7, an epigenetic regulator for H4K20me1 modification, was extensively expressed in the postnatal uteri, and its conditional deletion resulted in a complete lack of endometrial glands and infertility in mice. Subsequent analysis revealed that uterine PR-Set7 deficiency abolishes the dynamic endometrial epithelial population growth during the short span of gland formation from postnatal days 3 to 9. This markedly reduced epithelial population growth in PR-Set7-null mutant uteri is well associated with DNA damage accumulation and massive apoptotic death in the epithelium, due to blockade of 53BP1 recruitment to DNA damage sites upon reduced levels of H4K20me1/2. Using PgrCre/+/Rosa26DTA/+mouse line and postnatal progesterone injection mouse model, we further confirmed that an impaired epithelial cell population growth either by inducing epithelial death in the diphtheria toxin-A (DTA)-mouse model or attenuating epithelial growth upon postnatal progesterone treatment similarly hampers uterine adenogenesis. Collectively, we establish here a novel ‘epithelial population growth threshold’ model for successful gland development. Besides further shedding light on the regulatory machinery governing uterine gland formation, our findings raise a safety concern on progesterone supplementation to prevent preterm birth in women bearing a female fetus, as exogenous progesterone may hamper uterine adenogenesis via attenuating epithelial population growth.

来源: Cell Death & Differentiation 浏览次数:0

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