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Transcription factor interactions at the GH promoter

GH 启动子处的转录因子相互作用

基本信息

批准号：
7367018
负责人：
Fred J SCHAUFELE
金额：
$ 29.77万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2009-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367018
关键词：
Affect Anterior Pituitary Gland Binding Biochemical Biological Assay CCAAT-Enhancer-Binding Protein-alpha Cell Line Cell Nucleus Cells Centromere DNA DNA Binding Epigenetic Process Euchromatin Event Fluorescence Resonance Energy Transfer Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomics Goals Grant Growth Heterochromatin Histones Homeostasis Lead Location Marshal Metabolic Molecular Molecular Conformation Mutation Nuclear Nuclear Receptors Pan Genus Participant Pituitary Gland Positioning Attribute Prolactin Proteins Relative (related person)Research Personnel Rodent Satellite DNA Somatotropin Stem cells Structure Transcription Factor TFIIB Transcriptional Activation age related base cost gene synthesis growth hormone deficiency hormone therapy mutant normal aging novel prevent programs promoter transcription factor transcription factor Pit-1

项目摘要

DESCRIPTION (provided by applicant): Growth hormone is a central regulator of linear growth and metabolic homeostasis. GH synthesis is restricted transcriptionally to a subpopulation of ceils in the anterior pituitary gland. Our prior studies showed transcription of the evolutionary-related GH and prolactin (PRL) genes to be cooperatively activated by the pituitary-specific transcription factor Pit-1 and other transcription factors including CCAAT/enhancer binding protein alpha (C/EBPalpha). We found molecular interactions of Pit-1, C/EBPalpha, the coactivator CBP and the basal factors TBP and TFIIB to participate in cooperative activation. We also uncovered a pan-genomic layer to cooperative activity: C/EBPalpha is held inactive at pericentromeric heterochromatin through C/EBPalpha binding to alpha-satellite repetitive DNA. Pit-1 prevents C/EBPalpah binding to a-satellite DNA and thereby relocates C/EBPalpha to the transcriptionally active subcompartment of the cell nucleus. Such functional compartmentalization is emerging as an overlooked, epigenetic regulator of transcription Thus, Pit-1 both grants C/EBPalpha access to active genes and directly cooperates with C/EBPalpha at the GH and PRL promoters. The biochemical and functional inter-relationships between Pit- 1 release of C/EBPalpha from heterochromatin and direct synergy at the promoters remain to be defined. Our hypothesis is that pituitary-specific gene transcription results from distinct molecular interactions at the promoter that are regulated by the subnuclear compartmentalization of the interacting transcription factors and co-factors. Our goal is to define the molecular basis of the promoter-targeted and epigenetic layers and their relative contributions to synergy. We will: Aim 1. Compare the effects of mutations in specific Pit- l and C/EBPalpha activities on transcriptional synergy, release of C/EBPalpha binding to alpha-satellite DNA, and Pit-1 re-location of C/EBPalpha to euchromatin, Aim 2. Define the effects of the Pit-1 and C/EBPalpha mutants on the biochemical interactions of C/EBPalpha, Pit-l, and their relevant co-factors, Aim 3. Determine the effects of Pit- l and C/EBPalpha expression on biochemical recruitment of Pit- 1, C/EBPalpha and relevant co-factors specifically at the GH and PRL promoters and at alpha-satellite DNA.

描述（由申请人提供）：生长激素是线性生长和代谢稳态的中心调节剂。 GH 合成在转录上受到垂体前叶细胞亚群的限制。我们之前的研究表明，与进化相关的 GH 和催乳素 (PRL) 基因的转录是由垂体特异性转录因子 Pit-1 和其他转录因子（包括 CCAAT/增强子结合蛋白 α (C/EBPα)）协同激活的。我们发现 Pit-1、C/EBPα、共激活剂 CBP 以及基础因子 TBP 和 TFIIB 之间存在分子相互作用，参与协同激活。我们还发现了合作活动的泛基因组层：C/EBPα 通过与 α 卫星重复 DNA 结合，在着丝粒周围异染色质处保持非活性。 Pit-1 阻止 C/EBPalpah 与 a-卫星 DNA 结合，从而将 C/EBPalpha 重新定位到细胞核的转录活性亚区室。这种功能区划正在成为一种被忽视的表观遗传转录调节因子。因此，Pit-1 既允许 C/EBPα 接触活性基因，又在 GH 和 PRL 启动子处直接与 C/EBPα 合作。 Pit-1 从异染色质释放 C/EBPα 与启动子处的直接协同作用之间的生化和功能相互关系仍有待确定。我们的假设是，垂体特异性基因转录是由启动子处不同的分子相互作用引起的，这些相互作用受到相互作用的转录因子和辅助因子的亚核区室化的调节。我们的目标是定义启动子靶向层和表观遗传层的分子基础及其对协同作用的相对贡献。我们将：目标 1. 比较特定 Pit-1 和 C/EBPα 活性的突变对转录协同作用、C/EBPα 与 α-卫星 DNA 结合的释放以及 C/EBPα 到常染色质的 Pit-1 重定位的影响。目标 2. 定义 Pit-1 和 C/EBPα 突变体对 C/EBPα、Pit-1 及其相关辅因子的生化相互作用的影响，目标3.确定Pit-1和C/EBPα表达对Pit-1、C/EBPα和相关辅助因子(特别是在GH和PRL启动子以及α-卫星DNA处)的生化募集的影响。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CCAAT/enhancer binding protein alpha assembles essential cooperating factors in common subnuclear domains.

CCAAT/增强子结合蛋白α在共同的亚核结构域中组装重要的协同因子。

DOI：
10.1210/mend.15.10.0716
发表时间：
2001
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
0
作者：
Schaufele,F;Enwright3rd,JF;Wang,X;Teoh,C;Srihari,R;Erickson,R;MacDougald,OA;Day,RN
通讯作者：
Day,RN

Conformation of CCAAT/enhancer-binding protein alpha dimers varies with intranuclear location in living cells.

CCAAT/增强子结合蛋白α二聚体的构象随着活细胞核内位置的不同而变化。