NAT10 governs uterine function and fertility by stabilizing progesterone receptor mRNA via ac⁴C modification

TheN⁴-acetylcytidine (ac⁴C) modification is one of the most abundant chemical modifications in mammalian transcriptome, which plays a crucial role in regulating gene expression across various biological processes. In this study, we investigate the role ofN⁴-acetyltransferase 10 (NAT10), the sole enzyme responsible for catalyzing the ac⁴C modification, in uterine function. Our findings revealed that knockdown of NAT10 in cultured human endometrial stromal cells leads to decreased progesterone receptor (PGR) expression and compromised decidualization. Mechanistically, NAT10 is found to enhance the stability ofPGRmRNA through its ac⁴C modification in the coding sequence (CDS). Furthermore, conditional deletion ofNat10in the mouse uterus usingPgr-Cre resulted in defective pubertal uterine development, characterized by a thinner stroma and reduced endometrial gland number. These mice were infertile in adulthood, experiencing failures in both implantation and decidualization. However, heterozygousNat10conditional knockout mice showed reduced NAT10 expression in the uterus without affecting uterine development or fertility. To bridge the gap between heterozygous and homozygous knockout conditions, we employed Remodelin, an inhibitor of NAT10, in adult female mice, to mimic an intermediate gene dosage. Our results demonstrated that inhibiting NAT10 with Remodelin preserved uterine structures but disrupted the PGR signaling pathway, leading to impaired uterine function during pregnancy. In conclusion, our study provides compelling evidence that NAT10 safeguards uterine function and fertility by regulating the ac⁴C modification of PGR mRNA.