Mechanisms of transcriptional regulation and transcription factor specificity

转录调控机制和转录因子特异性

• 批准号: 10662197
• 负责人: Steven M Hahn
• 金额: $ 112.16万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662197
• 关键词: Address; Area; Binding; Biochemical; Cell physiology; Chromatin; Complex; Defect; Development; Gene Expression; Gene Expression Regulation; Genes; Genetic Enhancer Element; Genetic Transcription; Genomics; Human; Link; Mediator; Methods; Molecular; Pathway interactions; SAGA; Specificity; TAF1 gene; Technology; Time; Transcription Coactivator; Transcriptional Regulation; Work; cell growth; genome-wide; human disease; new technology; novel strategies; promoter; response; transcription factor

Summary Precise regulation of transcription is required for many cellular processes and misregulation of gene expression is linked to many human diseases. In prior work, great progress has been made in identifying important mechanisms and principles of transcriptional regulation. With this background, and using new technologies and approaches, this is an excellent time to tackle the next set of fundamental problems in gene regulation that have been difficult to address in prior work. Two related and important questions in the transcription field are: what are the primary mechanisms of gene regulation by sequence-specific transcription factors? and, how do these factors cooperate to orchestrate transcription of cellular genes? To address these questions, we will focus on three areas involving transcription factor and coactivator specificity and the activation mechanisms used at many genes: (i) Mechanisms leading to the genome-wide specificities of the coactivators TFIID and SAGA. Differential use of these coactivators defines two fundamental gene classes that dictate the mechanisms of preinitiation complex (PIC) assembly and the response to transcription factors and chromatin. (ii) The gene-specific functions of the coactivator Mediator in transcriptional regulation. At least two distinct pathways are used by transcription factors to modulate Mediator function that are transcription factor and promoter-specific, but the molecular basis of these mechanisms is not well understood. (iii) Mechanisms of transcription activator specificity and function. We will broaden our current studies on the function of acidic activation domains to examine mechanisms used by other widely used activator types and to examine how transcription factors bound at native UAS/enhancer elements cooperate. To address these fundamental problems, as in past work, we will use a combination of methods and technologies that include molecular, biochemical, genomic, computational, and structural approaches. In combination with our strong preliminary results, these new approaches and directions will reveal important conserved mechanisms and principles that illustrate how transcription factors, coactivators, chromatin, and the basal transcription machinery work together to modulate genome-wide transcription.

概括 许多细胞过程都需要精确的转录调节，而转录的错误调节 基因表达与许多人类疾病有关。在之前的工作中，已经取得了很大的进展 在确定转录调控的重要机制和原则方面取得了进展。有了这个 背景，并使用新技术和方法，这是解决这个问题的绝佳时机 基因调控中的下一组基本问题在以前很难解决 工作。转录领域中两个相关且重要的问题是：主要的是什么？ 序列特异性转录因子的基因调控机制？以及，这些如何 因素合作协调细胞基因的转录？为了解答这些问题，我们 将重点关注涉及转录因子和共激活子特异性的三个领域以及 许多基因使用的激活机制：（i）导致全基因组激活的机制 共激活剂 TFIID 和 SAGA 的特异性。这些共激活剂的不同使用定义了 决定预起始复合物 (PIC) 机制的两个基本基因类别 组装以及对转录因子和染色质的反应。 (ii) 基因特异性 共激活因子介体在转录调控中的功能。至少有两条不同的途径 被转录因子用来调节介体功能，即转录因子和 启动子特异性，但这些机制的分子基础尚不清楚。 (三) 转录激活剂特异性和功能的机制。我们将扩大目前的 研究酸性激活结构域的功能，以检查其他使用的机制 广泛使用的激活剂类型并检查转录因子如何与天然结合 无人机/增强器元件协作。为了解决这些基本问题，就像在过去的工作中一样， 我们将结合使用包括分子、生物化学、 基因组、计算和结构方法。结合我们强大的前期准备 结果，这些新方法和方向将揭示重要的保守机制和 说明转录因子、共激活因子、染色质和基础细胞如何发挥作用的原理 转录机器协同工作来调节全基因组转录。