权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Determining the mechanism of how GATA4 directs ERalpha binding in osteoblasts

确定 GATA4 如何指导成骨细胞中 ERα 结合的机制

基本信息

批准号：
9101991
负责人：
Susan A Miranda
金额：
$ 33万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-18 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9101991
关键词：
Ablation Adipocytes Affect Age American Antibodies Binding Binding Proteins Binding Sites Biological Assay Biology Bone Density Bone Development Bone Mineralization Regulation Pathway Brain ChIP-seq Chromatin DNA DNA Binding Deoxyribonucleases Dependence Disease Enhancers Estradiol Estrogen Receptor alpha Estrogens Event Female GATA4 gene Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Goals Hair Health Heterochromatin Histones Homeostasis In Vitro Knock-out Liver LoxP-flanked allele Maintenance Mammary Gland Parenchyma Mesenchymal Stem Cells Molecular Mus Mutagenesis Osteoblasts Osteocalcin Osteoporosis Osteoporosis prevention Outcome Physiologic calcification Play Postmenopausal Osteoporosis Postmenopause Proteins Recruitment Activity Reporter Genes Role Site Skin Specificity Technology Testing Time Tissues United States Woman Work bone bone cell bone mass cell type chromatin immunoprecipitation chromatin remodeling experience genome sequencing genome-wide histone modification in vivo insight malignant breast neoplasm mineralization novel osteoblast differentiation osteoporosis with pathological fracture prevent progenitor promoter recombinase reproductive organ research study response skeletal transcription factor whole genome

项目摘要

DESCRIPTION (provided by applicant): Estrogens are important for the maintenance of bone mineral density and the prevention of osteoporosis (or low bone mass), a disease that affects more than 29.5 million people in the United States. Estrogen receptor alpha (ER�), in response to estrogens, increases bone mineral density by increasing osteoblast proliferation and differentiation. GATA4, as a pioneer factor (a protein that can bind to target DNA within silent chromatin and initiate chromatin remodeling and helps recruit other transcription factors to the same locus), helps determine these tissue-specific effects of ER� gene regulation in osteoblasts. However, when and where GATA4 binds to DNA, and how GATA4 directs ER� binding to enhancers to regulate osteoblast differentiation is currently unknown. The central hypothesis of this proposal is that GATA4 increases differentiation of mesenchymal stem cells (MSCs) to osteoblasts by opening chromatin for ER� binding to enhancers. This hypothesis will be tested with the following three specific aims. Aim 1 will determine when during differentiation ER� and GATA4 are necessary to regulate osteoblast differentiation using temporally regulated gene expression in vitro and in vivo. Aim 2 will identify where ER� and GATA4 bind to DNA to regulate osteoblast differentiation using state-of-the-art high throughput, whole-genome sequencing technology. Aim 3 will elucidate the mechanism by which GATA4 regulates ER� binding to osteoblast enhancers. Together these experiments will for the first time describe how the novel osteoblast transcription factor GATA4 regulates estrogen biology in bone. These results will have valuable impact through characterization of ER� tissue-specificity in bone and hence will further understanding of how estrogens prevent osteoporosis.

描述（由申请人提供）：雌激素对于维持骨矿物质密度和预防骨质疏松症（或低骨量）非常重要，这种疾病影响着超过 2950 万美国人口。雌激素受体 α (ER�) 对雌激素作出反应，通过增加成骨细胞增殖和分化来增加骨矿物质密度。 GATA4 作为先锋因子（一种可以与沉默染色质内的目标 DNA 结合并启动染色质重塑并帮助将其他转录因子招募到同一位点的蛋白质），有助于确定 ER� 基因调控在成骨细胞中的这些组织特异性效应。然而，GATA4 何时何地与 DNA 结合，以及 GATA4 如何指导 ER� 与增强子结合以调节成骨细胞分化目前尚不清楚。该提议的中心假设是，GATA4 通过打开染色质使 ER� 与增强子结合来增加间充质干细胞 (MSC) 向成骨细胞的分化。该假设将通过以下三个具体目标进行检验。目标 1 将确定在分化过程中何时需要 ERβ 和 GATA4 使用体外和体内临时调节的基因表达来调节成骨细胞分化。目标 2 将利用最先进的高通量全基因组测序技术来确定 ER® 和 GATA4 与 DNA 结合的位置，以调节成骨细胞分化。目标 3 将阐明 GATA4 调节 ER� 与成骨细胞增强剂结合的机制。这些实验将首次描述新型成骨细胞转录因子 GATA4 如何调节骨骼中的雌激素生物学。这些结果将通过表征骨中 ER� 组织特异性产生有价值的影响，从而进一步了解雌激素如何预防骨质疏松症。