Estrogen Signaling and Estrogen Receptor Alpha Acetylation in the Pregnant Myometrium

妊娠子宫肌层中的雌激素信号传导和雌激素受体α乙酰化

• 批准号: 10063453
• 负责人: WILLIAM Lee KRAUS
• 金额: $ 24.22万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063453
• 关键词: Acetylation; Acetylesterase; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Biology; Birth; Cell Nucleus; Cells; ChIP-seq; Chromatin; Coitus; Computing Methodologies; Cultured Cells; DNA Binding; Deacetylase; Defect; EP300 gene; Enhancers; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Event; Gene Activation; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomics; Gonadal Steroid Hormones; Hormonal; Human; Knock-in Mouse; Ligands; Lysine; Maintenance; Mammals; Mediating; Methylation; Molecular; Molecular Biology; Monitor; Mus; Mutation; Myometrial; Outcome; Pathology; Pathway interactions; Pattern; Phosphorylation; Physiological; Physiological Processes; Physiology; Play; Post-Translational Protein Processing; Pregnancy; Premature Birth; Process; Production; Progesterone; Progesterone Receptors; Progestins; Prolonged labor; Proteins; RNA; Raloxifene; Reproduction; Role; SIRT1 gene; Series; Signal Pathway; Signal Transduction; Site; Specificity; Steroid Receptors; Testing; Therapeutic Intervention; Time; Tissues; Uterus; base; biochemical tools; cell type; estrogenic; experimental study; gain of function; genome-wide; genomic data; global run on sequencing; histone modification; mouse genetics; mouse model; myometrium; p300/CBP-Associated Factor; pregnant; prevent; protein function; receptor; receptor binding; recruit; reproductive; reproductive tract; steroid hormone; transcription factor; transcriptome; transcriptome sequencing

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.

项目摘要/摘要 - 项目2（KRAUS -PI） 晚期子宫肌层中雌激素和孕激素信号通路之间的相互作用 妊娠并在期限驱动导致分娩过程的物理过程基础的分子事件。 这些事件的缺陷或破坏可能导致过早分娩或延长劳动。雌激素的上升 妊娠晚期法案的水平为导致分娩的事件做准备的子宫肌计算（例如，增加 肌层收缩力）。但是，近期肌矩阵中雌激素作用的分子细节， 包括孕激素对肌层静止的维持的机制， 不清楚。雌激素（例如雌二醇，E2）和孕激素（例如孕酮，P4）通过类固醇作用 受体蛋白（雌激素受体，ER；孕激素受体，PR），起作用配体调节DNA 结合转录因子。 ERα的活性通过位点特异性共价翻译调节 修饰，包括赖氨酸266和268（在人类ERα中）的乙酰化，这两者都增加了DNA- ERα的结合和转录活性。 我们拟议的研究的长期目标是对关键方面有更好的了解 近期和分娩期间的雌激素信号传导的作用：（1）E2信号传导的作用 通过ERα，（2）E2-ERα拮抗P4--的分子机制 基因组水平的孕激素受体（PR），以及（3）ERα的分子机制 乙酰化控制子宫肌层中ERα依赖性基因调节。我们的假设是（1） 雌激素在肌层中的生理作用取决于基因组结合位点的曲目 （即“ Cistrome”）以及ERα以及由这些ERα结合位点调节的靶基因（增强子），（2） 通过ERα近期增加雌激素信号传导，部分通过改变PR来拮抗P4的作用 Cistrome和（3）乙酰化调节ERαCISTROME（例如形成，模式，特异性，稳定性），ERα 增强子组装和靶基因的表达。 在此提案中，我们使用综合方法在三个目标中概述了一系列实验 完全来自生物化学，分子生物学，基因组学，小鼠遗传学和生理学的工具集 这将检验我们的假设。总的来说，我们的研究将通过 配体ERα控制怀孕期间和期限。