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: 10397115
• 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/10397115
• 关键词: Address; Area; Biochemical; Cell physiology; Chromatin; Complex; Defect; Development; Gene Expression; Gene Expression Regulation; Genes; Genetic Enhancer Element; Genetic Transcription; Genomics; Human; Link; Mediator of activation protein; 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.

总结 转录的精确调节是许多细胞过程所必需的，而转录的错误调节是细胞的生理过程所必需的。 基因表达与许多人类疾病有关。在之前的工作中， 在确定转录调控的重要机制和原则。与此 背景，并使用新的技术和方法，这是一个很好的时间来解决 下一组基因调控的基本问题，在以前的研究中很难解决， 工作转录领域中两个相关的重要问题是： 序列特异性转录因子的基因调控机制？那么这些 这些因子协同协调细胞基因的转录？为了解决这些问题，我们 将集中在三个领域，涉及转录因子和辅激活因子的特异性和 在许多基因中使用的激活机制：（i）导致全基因组激活的机制 共激活剂TFIID和佐贺的特异性。这些辅活化剂的不同使用定义了 决定前起始复合体（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 辅激活因子介体在转录调控中的功能。至少有两种不同的途径 被转录因子用于调节作为转录因子的介体功能， 启动子特异性，但这些机制的分子基础还没有很好地理解。（三） 转录激活因子特异性和功能的机制。我们将扩大现有的 研究酸性激活结构域的功能，以检查其他 广泛使用的激活因子类型，并检查转录因子如何结合在天然的 UAS/增强器元件合作。为了解决这些基本问题，与过去的工作一样， 我们将使用包括分子，生物化学， 基因组、计算和结构方法。结合我们强大的初步 结果，这些新的方法和方向将揭示重要的保守机制， 这些原则说明了转录因子、辅激活因子、染色质和基底细胞如何在细胞中表达。 转录机制一起工作以调节全基因组转录。