Estrogen Signaling and Estrogen Receptor Alpha Acetylation in the Pregnant Myometrium

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Project Summary/Abstract - Project 2 (Kraus - PI) Interplay between the estrogen and progestin signaling pathways in the uterine myometrium during late gestation and at term drive the molecular events underlying the physiological processes leading to parturition. Defects in, or disruption of, these events can cause premature delivery or prolonged labor. Rising estrogen levels in late gestation act to prepare the myometrium for the events leading to parturition (e.g., increased myometrial contractility). However, the molecular details of estrogen action in the myometrium near term, including the mechanisms by which it antagonizes the maintenance of myometrial quiescence by progestins, are unclear. Estrogens (e.g., estradiol, E2) and progestins (e.g., progesterone, P4) act through steroid receptor proteins (estrogen receptors, ERs; progestin receptors, PR), which function as ligand-regulated DNA binding transcription factors. The activity of ERα is modulated through site-specific covalent post-translational modifications, including acetylation at lysines 266 and 268 (in human ERα), which increases both the DNA- binding and transcriptional activities of ERα. The long-term objectives of our proposed studies are to achieve a better understanding of key aspects of estrogen signaling in the myometrium near term and during parturition, namely: (1) the role of E2 signaling through ERα, (2) the molecular mechanisms by which E2-ERα antagonizes the progestational actions of P4- progestin receptor (PR) at the level of the genome, and (3) the molecular mechanisms by which ERα acetylation controls ERα-dependent gene regulation in the myometrium. Our hypotheses are that (1) the physiological actions of estrogens in the myometrium are determined by the repertoire of genomic binding sites (i.e., “cistrome”) for ERα, as well as the target genes regulated by those ERα binding sites (enhancers), (2) increased estrogen signaling through ERα near term antagonizes P4 actions, in part, by altering the PR cistrome, and (3) acetylation regulates the ERα cistrome (e.g., formation, pattern, specificity, stability), ERα enhancer assembly, and the expression of target genes. In this proposal, we outline a series of experiments in three aims using an integrated approach with a complementary set of tools from biochemistry, molecular biology, genomics, mouse genetics, and physiology that will test our hypotheses. Collectively, our studies will reveal new aspects of the molecular mechanisms by which liganded ERα controls the biology of the myometrium during pregnancy and at term.