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: 10164063
• 负责人: Steven M Hahn
• 金额: $ 101.69万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164063
• 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; Structure; 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 许多细胞过程需要进行转录的精确调节，并造成不利 基因表达与许多人类疾病有关。在先前的工作中，取得了长足的进步 在识别重要机制和转录调节原理方面制作的。与此 背景以及使用新技术和方法，这是解决问题的绝佳时机 基因调节中的下一组基本问题，在先验中很难解决 工作。转录字段中的两个相关和重要的问题是：主要问题是什么 通过序列特异性转录因子调节基因调节的机制？而且，如何 合作协调细胞基因转录的因素？为了解决这些问题，我们 将专注于涉及转录因子和共激活因子特异性的三个领域以及 在许多基因上使用的激活机制：（i）导致全基因组的机制 共激活器的特异性TFIID和SAGA。这些共激活器的差异使用定义 两个基本基因类别决定了前启动复合物的机制（PIC） 组装以及对转录因子和染色质的反应。 （ii）基因特异性 共激活因子在转录调节中的功能。至少两个不同的途径 转录因子使用用于调节转录因子的介体功能，并且 启动子特异性，但是这些机制的分子基础尚不清楚。 （iii） 转录激活剂的特异性和功能的机制。我们将扩大我们的当前 研究酸性活化域的功能，以检查其他人使用的机制 广泛使用的激活剂类型，并检查转录因子如何结合天然 UAS/增强子元素合作。为了解决这些基本问题，就像过去的工作一样， 我们将使用包括分子，生化，包括分子的方法和技术的组合 基因组，计算和结构方法。结合我们强大的初步 结果，这些新方法和方向将揭示重要的保守机制，并 说明转录因子，共激活因子，染色质和基础的原则 转录机械共同调节全基因组转录。