Role of eukaryotic transcription regulators in the regulation of stochastic gene expression

生物体的基因如何、何时以及在何种程度上受到调控，这些难题的答案构成了所有生物物种繁殖和进化的关键决定因素。因此，任何导致这种调节功能失调的事件都不可避免地会促进癌症等疾病的发生。在过去十年左右的时间里，我们对控制基因表达的分子机制的理解取得了巨大的进步。基因特异性转录因子需要接近其调控靶点，以调节基因的表达。为了实现这种调节，必须首先在给定基因上适当地将染色质重塑为预设的激活或抑制状态。我实验室的长期目标是了解转录因子如何在染色质环境中发挥作用，从而在适当的生理提示下引发转录反应。研究转录因子在基因表达中的功能的经典方法使用的技术旨在测量细胞群体的基因表达水平。然而，最近的实验表明，基因表达的随机波动在细胞之间发生，因此使细胞容易发生细胞行为的变异性。我们现在的工作将包括研究各种类型的转录因子（即激活因子和辅激活因子）的重要性，以及组蛋白修饰，在“细胞对细胞”的背景下调节基因表达，以及它如何促进随机基因表达。为此，我们将利用荧光报告分析，结合遗传和染色质免疫沉淀方法。我坚信，这项研究计划将揭示在细胞群体中发生的基因调控的重要新机制。

The answer to the conundrum of how, when, and to what level genes of living organisms are regulated constitutes the key determinant of all biological species' propagation and evolution.  Hence any event that leads to the dysfunction of this regulation can inevitably promote diseases such as cancer.  In the last decade or so, colossal advances have been made in our understanding of the molecular mechanisms that control gene expression.  Gene-specific transcription factors need to access their regulatory targets in order to modulate the expression of genes.  To achieve this regulation, chromatin must first be appropriately remodeled to preset activation or repression states at a given gene.  The long-term goal of my laboratory is to understand how transcription factors function in a chromatin environment to elicit a transcription response under an appropriate physiological cue.Classical ways of studying the function of transcription factors in gene expression have used technologies that were aimed at measuring gene expression levels of a population of cells.  However, recent experiments have now shown that random fluctuations in gene expression occurred from cell to cell, therefore making cells prone to variability in cellular behavior.  Our work will now consist of studying the importance of various types of transcription factors (i.e. activators and coactivators), as well as histone modifications, in regulating gene expression in a 'cell-to-cell' context, and how that contributes to stochastic gene expression.  For this, we will make use of fluorescent reporter assays, coupled with genetic and chromatin immunoprecipitation approaches.    It is my firm belief that this research program will reveal important new mechanisms of gene regulation that occur within a population of cells.