Molecular and Genomic Mechanisms in the Biology of Pregnancy and Parturition

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PROJECT SUMMARY/ABSTRACT In this new program project, we will utilize comprehensive global genomic approaches (RNA sequencing [RNA-seq], global run-on sequencing [GRO-seq], and chromatin immunoprecipitation sequencing [ChIP-seq]) to understand the biological mechanisms for term and preterm birth. This application is timely, because of the huge advances in genomic technologies combined with cutting-edge computational tools, which have dramatically advanced our understanding of signal-regulated gene transcription in a wide variety of biological systems. The global views generated by these assays provide a uniquely informative biological perspective that cannot be achieved by analyzing one or even a few genes at a time. We propose to utilize these state-of-the-art techniques to develop an in-depth understanding of the genomic and epigenomic mechanisms that underlie the regulation of myometrial quiescence-contractility, cervical competency-dilation, and that maintain barrier function of the cervix to protect the pregnancy against invading microorganisms and prevent prematurity. The P01 includes four interrelated projects: Project 1: Epigenetic Regulation of Myometrial Contractility in Pregnancy and Labor (Carole R. Mendelson); Project 2: Functional Roles of Estrogen Receptor α Acetylation in the Uterus (W. Lee Kraus); Project 3: Genomic Consequences of Estrogen Receptor Activation in the Cervix (R. Ann Word); Project 4: Mechanisms of Cervical Epithelial Barrier Protection Against Ascending Infection and Preterm Birth (Mala S. Mahendroo), supported by three cores: Administrative Core (Mendelson); Genomics and Computational Core (Kraus); Human Tissue and Biological Fluid Acquisition Laboratory Core (Word). The goals of these projects are: Project 1 - to define the genes and mechanisms that underlie the actions of progesterone (P4), via progesterone receptor isoforms, PR-A and PR-B, on inflammatory and `contractile' gene expression, and to characterize the chromatin modifications that mediate myometrial quiescence and accompany enhanced contractile gene expression leading to term and preterm labor; Project 2 - to achieve a better understanding of the biology of estrogen signaling through estrogen receptor α (ERα) in the female reproductive tract during pregnancy and parturition by elucidating the role of ERα acetylation in the function of the uterus and cervix of pregnant females and the molecular mechanisms by which ERα acetylation controls ERα-dependent gene regulation in these tissues; Project 3 - to understand the mechanisms by which PRs and ERs interact to alter gene expression, gestational length, and structural integrity of the cervix during pregnancy, cervical ripening and parturition, and; Project 4 – to utilize genomic, cell biological and biochemical approaches to advance our understanding of the mechanisms by which hyaluronan (HA) provides immune- protection and epithelial barrier function in the pregnant cervix, as well as the molecular mechanisms whereby HA synthase 2 is regulated. We propose that these interrelated projects, carried out by a highly interactive research team, will achieve our long-range goal of reducing the incidence of preterm birth.