Myometrial progesterone receptor determines a transcription program for uterine remodeling and contractions during pregnancy

Abstract

Abstract The uterine myometrium expands and maintains contractile quiescence before parturition. While the steroid hormone progesterone blocks labor, the role of progesterone signaling in myometrial expansion remains elusive. This study investigated the myometrial functions of the progesterone receptor, PGR. Pgr ablation in mouse smooth muscle leads to subfertility, oviductal embryo retention, and impaired myometrial adaptation to pregnancy. While gross morphology between mutant and control uteri are comparable, mutant uteri manifest a decrease of 76.6% oxytocin-stimulated contractility in a pseudopregnant context with a reduced expression of intracellular calcium homeostasis genes including Pde5a and Plcb4. At mid-pregnancy, the mutant myometrium exhibits discontinuous myofibers and disarrayed extracellular matrix at the conceptus site. Transcriptome of the mutant mid-pregnant uterine wall manifests altered muscle and extracellular matrix profiles and resembles that of late-pregnancy control tissues. A survey of PGR occupancy, H3K27ac histone marks, and chromatin looping annotates cis-acting elements that may direct gene expression of mid-pregnancy uteri for uterine remodeling. Further analyses suggest that major muscle and matrix regulators Myocd and Ccn2 and smooth muscle building block genes are PGR direct downstream targets. Cataloging enhancers that are topologically associated with progesterone downstream genes reveals distinctive patterns of transcription factor binding motifs in groups of enhancers and identifies potential regulatory partners of PGR outside its occupying sites. Finally, conserved correlations are found between estimated PGR activities and RNA abundance of downstream muscle and matrix genes in human myometrial tissues. In summary, PGR is pivotal to direct the molecular program for the uterus to remodel and support pregnancy.