Abstract
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.
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Acknowledgements
We are grateful to Dr. Francesco DeMayo (National Institute of Environmental Health Sciences, USA) for his generosity in providing us with the PgrCre/+ mice. This work was supported by National Key R&D Program of China (2017YFC1001402 to HW, 2017YF0104603 to SK and JL) and the National Natural Science Foundation (81330017 and 81490744 to HW, 81601285 to SK and 31600945 to JL).
Author contributions
WH and LJ designed research; CT, HB, KS, ZC, NZ and BH performed research; WH, LJ, CT, ZH, QJ and XQ analyzed the data; DR and JPL provided mouse models; CT, LJ and WH wrote the paper.
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Cui, T., He, B., Kong, S. et al. PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice. Cell Death Differ 24, 2013–2021 (2017). https://doi.org/10.1038/cdd.2017.120
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DOI: https://doi.org/10.1038/cdd.2017.120
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