PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice
PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice
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PR-Set7 缺陷限制子宫上皮细胞群生长，阻碍小鼠产后腺体形成
DOI：
10.1038/cdd.2017.120
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发表时间：
2017-12-01
影响因子：
12.4
通讯作者：
Wang, Haibin
中科院分区：
文献类型：
--
作者：
Cui, Tongtong;He, Bo;Wang, Haibin
子宫内分泌性子宫内膜腺的形成称为腺发生，是一个典型的分支形态发生过程，涉及上皮细胞的动态生长和分化。不成功的性腺发生往往会导致女性不孕。然而，迄今为止，关于正常子宫内膜腺体形成的表观遗传机制仍未被探索。在这里，我们证明了PR-Set 7，一种H4 K20 me 1修饰的表观遗传调节因子，在出生后子宫中广泛表达，其条件性缺失导致小鼠完全缺乏子宫内膜腺体和不育。随后的分析表明，子宫PR-Set 7缺陷废除动态子宫内膜上皮细胞群体的增长在短期内的腺体形成从出生后第3至9天。由于H4 K20 me 1/2水平降低后53 BP 1募集到DNA损伤位点的阻断，PR-Set 7缺失突变子宫中上皮细胞群体生长的显着减少与上皮细胞中DNA损伤累积和大量细胞凋亡死亡密切相关。使用Pgr Cre/+/Rosa 26 DTA/+小鼠系和出生后注射孕酮的小鼠模型，我们进一步证实了通过在白喉毒素-A（DTA）-小鼠模型中诱导上皮死亡或在出生后孕酮处理后减弱上皮生长而损害的上皮细胞群体生长类似地阻碍子宫腺发生。总的来说，我们在这里建立了一个新的“上皮细胞群体生长阈值”模型，成功的腺体发育。除了进一步阐明控制子宫腺形成的调节机制外，我们的研究结果还提出了补充孕酮以预防女性胎儿早产的安全性问题，因为外源性孕酮可能通过减弱上皮细胞群生长而阻碍子宫腺发生。
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 Pgr Cre/+/Rosa26 DTA/+ 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.