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

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 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.

SUBMITTER: Cui T 

PROVIDER: S-EPMC5686342 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature