Plasticity of X-chromosome inactivation in female reproduction

X-chromosome inactivation (XCI) is a mammalian mechanism for dosage compensation, yet its dynamics across reproductive states remain poorly characterized. Here we identify XCI plasticity in female reproductive tissues, including the endometrium and maternal immune cells. Single-cell transcriptomic analyses show that proliferating endometrial stromal cells exhibit the highest silenced-to-escape expression ratio (STER)—a relative measure of expression balance between XCI-silenced and canonical escape X-linked genes—accompanied by reduced allelic imbalance of silenced genes, before sharply declining during decidualization. In contrast, maternal immune cells maintain a low STER with increased XIST expression across gestation. Epigenetic profiling reveals increased biallelic demethylation of silenced genes during endometrial proliferation. This biallelic demethylation is reduced in maternal blood during healthy gestation but increased in complicated pregnancies and in nulliparous women. Cross-species analyses reveal similar XCI plasticity in subfertile cattle and strong correlations between baseline XCI dynamics and lifetime reproductive potential across mammals. Together, these findings establish XCI plasticity as a dynamic feature of mammalian reproduction.