Analysis of divergent transcripts in estrogen-dependent signaling.

项目摘要 内分泌激素雌激素（E2）通过结合其雌激素受体α（ERα）发挥作用，刺激 在ER+细胞中有强烈的促有丝分裂反应。在这方面，信号调节的趋异转录及其产物 已经成为一类重要的分子，调节各种内分泌途径， 和雄激素信号。最近的研究表明，不同的转录本是细胞和组织特异性的 表达，并且E2调节的趋异转录对于引发完全E2驱动的基因表达至关重要。E2 信号传导触发高度协调的转录程序，导致强大的促有丝分裂反应， 不同的细胞活动。理解不同转录或 转录物调控E2应答，ERα依赖的转录将增加我们对疾病的理解 由异常的E2信号引起解读不同转录本在细胞内作用的分子机制 ER+细胞将非常重要。在涉及细胞和基因组方法的初步研究中， 鉴定并注释了受调节的趋异RNA。此外，初步表征了一种新的E2- 受调节的趋异转录物表明它控制E2驱动的细胞过程和基因表达。在 目前的建议，不同的转录本调节E2依赖的信号转导的分子机制将 被确定。最重要的假设是，不同的生物化学和结构特性， 转录物是它们控制关键的E2依赖性途径的能力的基础。一套互补的生化， 分子、细胞、蛋白质组和基因组分析将用于研究 趋异转录本调节E2依赖的转录和ER+细胞的生长：具体地说，（1）Aim 1将 确定E2调节的趋异转录物在E2依赖性信号传导中的分子作用机制， （2）目的2将确定趋异转录本控制E2依赖的 基因调控复合体成功完成这些目标将产生一个新的理解， 转录物控制关键的E2依赖性细胞通路。

Project Summary The endocrine hormone estrogen (E2) actions by binding to its estrogen-receptor alpha (ERα), stimulates a robust mitogenic response in ER+ cells. In this regard, signal-regulated divergent transcription and its products have emerged as an important class of molecules that regulate various endocrine pathways such as estrogen and androgen signaling. Recent studies suggest that divergent transcripts are cell- and tissue-specifically expressed, and the E2-regulated divergent transcription is critical to eliciting full E2-driven gene expression. E2 signaling triggers a highly coordinated transcriptional program, leading to a robust mitogenic response that drives different cellular activities. Understanding the molecular mechanisms through which divergent transcription or transcripts regulate E2-responsive, ERα-dependent transcription will increase our understanding of the diseases caused by aberrant E2-signaling. Deciphering the molecular mechanisms of action of divergent transcripts in ER+ cells will be very important. In the preliminary study involving cellular and genomic approaches, E2- regulated divergent RNAs were identified and annotated. In addition, the initial characterization of a novel E2- regulated divergent transcript suggests that it controls E2-driven cellular processes and gene expression. In the current proposal, the molecular mechanisms by which divergent transcripts regulate E2-dependent signaling will be determined. The overarching hypothesis is that specific biochemical and structural properties of divergent transcripts underlie their ability to control critical E2-dependent pathways. A complementary set of biochemical, molecular, cell-based, proteomic, and genomic assays will be used to study the molecular mechanisms by which divergent transcript regulates E2-dependent transcription and growth of ER+ cells: specifically (1) Aim 1 will determine the molecular mechanisms of action of E2-regulated divergent transcript, in E2-dependent signaling, and (2) Aim 2 will identify the mechanism by which divergent transcripts control the assembly of E2-dependent gene regulatory complex. Successful completion of these aims will yield a new understanding of how divergent transcripts control key E2-dependent cellular pathways.