PR-SET7 is indispensable for epigenetically silencing uterine interferon response and cell death governing normal postnatal stromal development

The spatiotemporal changes and underlying regulatory mechanisms of postnatal uterine stromal development remain largely elusive. In the present study, we comprehensively delineated the dynamic development of the neonatal uterus at single-cell resolution, and characterized two stromal subpopulations, inner and outer stromal cells, with distinct distributions and features. Furthermore, single-cell RNA sequencing (scRNA-seq) analysis revealed that uterine ablation of Pr-set7, the sole methyltransferase catalyzing mono-methylation of H4K20 (H4K20me1), led to reduced proportion and compromised specification of inner stromal cells, which vanished eventually due to massive cell death, thus impeding uterine development. Detailed investigations employing bulk RNA-seq and genome-wide epigenetic profiling for H4K20me1 demonstrated that PR-SET7-mediated H4K20me1 either directly repressed the expression of certain interferon stimulated genes (ISGs) or indirectly restricted overwhelming anti-viral responses via silencing endogenous retroviruses (ERVs) during postnatal uterine development. Declined H4K20me1 level gave rise to hyperactivated viral mimicry reactions and culminated in ZBP1-mediated apoptosis and necroptosis. Collectively, our study provided an unprecedented insight into the epigenetic machinery governing postnatal uterine stromal development mediated by PR-SET7 and H4K20me1.