An epigenetic timer of gestation length in mice [scRNA-Seq]

Timing mechanisms in biology remain poorly understood. As one prime example, little is known about the mechanisms that specify how long the gestating uterus will remain quiescent before entering labor1. Our lack of insight into this fundamental question, which applies to all mammalian species, also limits investigation into potential causes of preterm labor, a major human pregnancy complication. Here, we provide evidence that gestation length in mice is determined by an epigenetic timer that runs autonomously within the fibroblasts of the pregnant uterus. The timer is set during the peri-implantation period when select genomic loci establish appropriate levels of the repressive histone mark H3K27me3. These loci then progressively lose H3K27me3, thereby scheduling the uterine cell state transitions and associated gene expression changes of late gestation that are the proximal mediators of labor onset. Overwinding of the timer’s peri-implantation setpoint via genetic ablation of the histone demethylase KDM6B delays these transitions and extends gestation length. These results provide insight into how complex tissues employ epigenetic pathways to specify the timing of discrete biological events. We also anticipate that further dissection of the ways such uterine programming controls gestation length may suggest novel approaches for improving human pregnancy outcomes.