Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
Nat Commun. 2024 Jun 10;15(1):4920. doi: 10.1038/s41467-024-49342-6.
The differentiation of the stroma is a hallmark event during postnatal uterine development. However, the spatiotemporal changes that occur during this process and the underlying regulatory mechanisms remain elusive. Here, we comprehensively delineated the dynamic development of the neonatal uterus at single-cell resolution and characterized two distinct stromal subpopulations, inner and outer stroma. Furthermore, single-cell RNA sequencing revealed that uterine ablation of Pr-set7, the sole methyltransferase catalyzing H4K20me1, led to a reduced proportion of the inner stroma due to massive cell death, thus impeding uterine development. By combining RNA sequencing and epigenetic profiling of H4K20me1, we demonstrated that PR-SET7-H4K20me1 either directly repressed the transcription of interferon stimulated genes or indirectly restricted the interferon response via silencing endogenous retroviruses. Declined H4K20me1 level caused viral mimicry responses and ZBP1-mediated apoptosis and necroptosis in stromal cells. Collectively, our study provides insight into the epigenetic machinery governing postnatal uterine stromal development mediated by PR-SET7.
基质的分化是产后子宫发育过程中的一个标志性事件。然而，这一过程中发生的时空变化及其潜在的调节机制仍难以捉摸。在这里，我们全面描绘了单细胞分辨率下新生子宫的动态发育，并对两个不同的基质亚群进行了特征描述，即内基质和外基质。此外，单细胞 RNA 测序显示，Pr-set7 是唯一催化 H4K20me1 的甲基转移酶，其在子宫中的缺失会导致内基质比例减少，这是由于大量细胞死亡，从而阻碍了子宫的发育。通过结合 RNA 测序和 H4K20me1 的表观遗传特征分析，我们证明 PR-SET7-H4K20me1 可以直接抑制干扰素刺激基因的转录，或通过沉默内源性逆转录病毒间接限制干扰素反应。H4K20me1 水平的下降导致了基质细胞中的病毒模拟反应以及 ZBP1 介导的细胞凋亡和坏死。总的来说，我们的研究提供了对 PR-SET7 介导的产后子宫基质发育的表观遗传机制的深入了解。
