Mechanisms of coordinate gene regulation by transcription factors

转录因子协调基因调控的机制

• 批准号: 10441975
• 负责人: Michael Joseph Guertin
• 金额: $ 41万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441975
• 关键词: Address; Biological Process; Cell Death; Cellular Stress; Complex; Computing Methodologies; Cues; Data; Development; Disease; Dominant-Negative Mutation; Environmental Risk Factor; Estrogen Receptors; Estrogen Therapy; Estrogens; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Individual; Kinetics; Lead; Light; Mediating; Modeling; Molecular; Organism; Peptides; Pharmaceutical Preparations; Regulation; Regulatory Element; Repression; Research; Signal Transduction; Specificity; Statistical Models; System; Testing; Time; Transcriptional Regulation; Variant; Work; cofactor; developmental disease; ineffective therapies; inhibitor/antagonist; nutrition; programs; response; temporal measurement; transcription factor

ABSTRACT Many of the molecular mechanisms underlying well-characterized robust and rapidly inducible transcriptional responses are shared among other systems, so we use the transcriptional response to estrogen treatment as a model to study gene regulation. We use rapid kinetic regulation and perturbation of transcription cascades, transcription factors, and cofactors to identify key mechanisms, genes, and regulatory elements that are critical for estrogen signaling. Transcription factors act as activators or repressors and interface with a constellation of accessory cofactors to regulate distinct steps in the transcription to coordinate gene expression, but the molecular functions of the vast majority of transcription factors remain uncharacterized. We will use molecular genomics and computational methods to classify transcription factors by their molecular function, as opposed to broad activator and repressor classes, in order to understand the context specificity of gene regulation. We recently found that the estrogen receptor transcription factor may compete with other transcription factors for limiting cofactors to mediate estrogen-induced repression. We will develop light inducible dominant negative peptide inhibitors to test various models of repression and address the challenges of studying estrogen- repressed genes. The genes and regulatory elements that are downstream of the first wave of transcriptional response are critical for propagating regulatory cascades. We will generate high temporal resolution time course data and implement statistical modeling approaches to identify effector genes and regulatory elements that are critical for estrogen signaling. Our research will continue to reveal basic principles and rules that govern transcription factor specificity in order to someday understand how genetics, nutrition, and environmental factors contribute to variation in transcriptional programs that can lead to disease states or ineffective therapies.

抽象的 许多分子机制已被充分表征，具有强大且快速诱导的转录能力 反应在其他系统之间共享，因此我们使用雌激素治疗的转录反应作为 研究基因调控的模型。我们使用转录级联的快速动力学调节和扰动， 转录因子和辅助因子，用于识别至关重要的关键机制、基因和调控元件 用于雌激素信号传导。转录因子充当激活剂或阻抑剂，并与一系列相互作用 辅助辅因子调节转录中的不同步骤以协调基因表达，但是 绝大多数转录因子的分子功能仍然未知。我们将使用分子 基因组学和计算方法根据转录因子的分子功能对其进行分类，而不是 广泛的激活子和阻遏子类别，以了解基因调控的背景特异性。我们 最近发现雌激素受体转录因子可能与其他转录因子竞争 限制辅助因子介导雌激素诱导的抑制。我们将开发光诱导显性负性 肽抑制剂来测试各种抑制模型并解决研究雌激素的挑战 被压抑的基因。第一波转录波下游的基因和调控元件 反应对于传播监管级联至关重要。我们将生成高时间分辨率的时间 课程数据并实施统计建模方法来识别效应基因和调控元件 这对于雌激素信号传导至关重要。我们的研究将继续揭示基本原则和规则 控制转录因子的特异性，以便有朝一日了解遗传学、营养学和 环境因素导致转录程序的变化，从而导致疾病状态或 无效的治疗方法。