Mechanisms of transcriptional regulation and transcription factor specificity

摘要 转录的精确调控是许多细胞过程所必需的，也是转录调控不当所必需的 基因表达与许多人类疾病有关。在前期工作中，取得了很大进展。 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，并使用新的技术和方法，这是解决 下一组基因调控中的基本问题，这些问题在以前的 工作。转录领域中两个相关而重要的问题是：什么是主要的 序列特异性转录因子调控基因的机制？那么，这些是如何 协调细胞基因转录的因素是什么？为了解决这些问题，我们 将集中在涉及转录因子和辅活化子特异性的三个领域，以及 许多基因使用的激活机制：(I)导致全基因组范围的 共激活子TFIID和SAGA的特性。这些助活剂的不同使用定义了 决定预引发复合体(PIC)机制的两个基本基因类 组装以及对转录因子和染色质的反应。(Ii)特定基因 共激活因子介体在转录调控中的作用。至少有两条不同的路径 被转录因子用来调节介体功能，即转录因子和 启动子特异，但这些机制的分子基础还不是很清楚。(Iii) 转录激活剂的专一性和作用机制。我们将扩大我们目前的 酸性活化区对检测其他细菌作用机制的研究 广泛使用的激活剂类型，并研究转录因子如何与天然的 UAS/增强器元素合作。为了解决这些根本问题，就像过去的工作一样， 我们将使用多种方法和技术相结合，包括分子、生化、 基因组、计算和结构方法。结合我们强有力的初步调查 结果，这些新的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 转录机器协同工作来调节全基因组的转录。

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.