During gestation, uterine smooth muscle cells transition from a state of quiescence to one of contractility, but the molecular mechanisms underlying this transition at a genomic level are not well-known. To better understand these events, we evaluated the epigenetic landscape of the mouse myometrium during the pregnant, laboring, and postpartum stages. We generated gestational time point–specific enrichment profiles for histone H3 acetylation on lysine residue 27 (H3K27ac), histone H3 trimethylation of lysine residue 4 (H3K4me3), and RNA polymerase II (RNAPII) occupancy by chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq), as well as gene expression profiles by total RNA-sequencing (RNA-seq). Our findings reveal that 533 genes, including known contractility-driving genes (Gap junction alpha 1 [Gja1], FBJ osteosarcoma oncogene [Fos], Fos-like antigen 2 [Fosl2], Oxytocin receptor [Oxtr], and Prostaglandin G/H synthase 2 (Ptgs2), for example), are up-regulated at day 19 during active labor because of an increase in transcription at gene bodies. Labor-associated promoters and putative intergenic enhancers, however, are epigenetically activated as early as day 15, by which point the majority of genome-wide H3K27ac or H3K4me3 peaks present in term laboring tissue is already established. Despite this early exhibited histone signature, increased noncoding enhancer RNA (eRNA) production at putative intergenic enhancers and recruitment of RNAPII to the gene bodies of labor-associated loci were detected only during labor. Our findings indicate that epigenetic activation of the myometrial genome precedes active labor by at least 4 days in the mouse model, suggesting that the myometrium is poised for rapid activation of contraction-associated genes in order to exit the state of quiescence.

在妊娠期间，子宫平滑肌细胞从静止状态转变为可收缩状态，但是在基因组水平上这种转变所基于的分子机制尚不清楚。为了更好地了解这些事件，我们评估了在怀孕，分娩和产后阶段小鼠子宫肌层的表观遗传景观。我们通过大规模平行测序的染色质免疫沉淀法（ChIP- seq），以及通过总RNA测序（RNA-seq）获得的基因表达谱。我们的发现揭示了533个基因，包括已知的收缩力驱动基因（Gap联结alpha 1 [Gja1 ]，FBJ骨肉瘤癌基因[ Fos ]，Fos样抗原2 [ Fosl2 ]，催产素受体[ Oxtr ]和前列腺素G / H合酶2（Ptgs2，例如），由于活跃在分娩期的第19天，由于基因体的转录增加而被上调。然而，早在第15天就与表观遗传激活了与劳动相关的启动子和推定的基因间增强子，到那时，已经确定了在长期劳动组织中存在的大多数全基因组范围的H3K27ac或H3K4me3峰。尽管这种早期表现出组蛋白签名，但仅在分娩期间才检测到推定的基因间增强子上非编码增强子RNA（eRNA）的产生增加以及将RNAPII募集到与分娩相关的基因座中。我们的发现表明，在小鼠模型中，子宫肌层基因组的表观遗传激活比活跃劳动提前了至少4天，