Gene regulatory functions of co-transcriptional histone modifications

我实验室的研究重点是了解基因是如何开启和关闭的。精确的基因调控是人类（和所有生物）许多重要生物学功能的基础，包括细胞生长、细胞分裂和发育过程中适当细胞身份的建立。基因是通过一个高度复杂的多步骤过程开启的。我们对这个过程的一些早期步骤很感兴趣，在这个过程中，蛋白质机器与染色体DNA结合，并将其作为模板来复制信使RNA。这个过程被称为转录，在细胞中受到高度调控。为了使转录正常进行，染色体DNA需要能够被携带它的蛋白质接触到，这就需要改变和重排被称为组蛋白的关键DNA包装蛋白。有趣的是，组蛋白修饰和组蛋白dna结构的重排是一种固有的能力，在进行转录的蛋白质机制中。它采用的一个重要机制是对组蛋白进行化学修饰，改变它们的性质以促进转录。组蛋白上发生的化学修饰是多种多样的。引人注目的是，伴随转录的组蛋白修饰模式在进化中是高度保守的，几乎在每个基因上都是相同的。这表明该模式在转录过程中起着重要作用（或多个角色），尽管定义它是什么一直具有挑战性。干扰这种模式的一个重要后果是，转录往往发生在不适当的位置，导致产生异常rna，这已经在基因操纵模式生物的实验中得到了证实。我们建议研究组蛋白修饰的转录“景观”。我们的研究将采用一种简单的模式生物，裂变酵母，它可以很容易地生长和基因操作。重要的是，分裂酵母中的组蛋白修饰景观几乎与人类细胞中的相同。该研究计划有两个主要目标：1。确定组蛋白修饰如何调控基因表达。为此，我们将使用详细的生化实验来评估修饰组蛋白和一系列基因修饰酵母菌株的功能。2.确定基因调控“异常”转录的后果。为了做到这一点，我们将使用技术来监测整个基因组中发生异常转录的位置。通过这些研究，我们将对与组蛋白修饰相关的基因调控机制有新的、基本的见解。我们还将获得关于组蛋白修饰模式缺陷如何破坏基因调控的宝贵知识。

Research in my lab is focused on understanding how genes are turned on and off. Precise gene regulation underlies many important biological functions in humans (and all organisms), including cell growth, cell division, and establishment of proper cell identity during development. Genes are turned on through a highly complex multi-step process. We are interested in some of the early steps in this process, in which protein machines engage with chromosomal DNA and use it as a template to make messenger RNA copies. This process, termed transcription, is highly regulated in cells. For transcription to happen properly, chromosomal DNA needs to be accessible to the proteins that carry it out, and this requires alteration and rearrangement of key DNA packaging proteins called histones. Interestingly, histone modification and rearrangement of histone-DNA structures is an ability that is inherent in within the protein machinery that carries out transcription. An important mechanism that it employs is chemical modification of the histones, which changes their properties to facilitate transcription. The chemical modifications that occur on histones are diverse. Strikingly, patterns of histone modifications that accompany transcription are highly conserved in evolution and are virtually identical at every gene. This suggests that the pattern plays an important role (or roles) in the transcription process, although defining what this is has been challenging. One important consequence of interfering with this pattern, which has been done in experiments with genetically manipulated model organisms, is that transcription tends to happen in inappropriate locations, leading to production of aberrant RNAs. We propose to study the histone modification "landscape" of transcription. Our studies will employ a simple model organism, fission yeast, which can be easily grown and manipulated genetically. Importantly, the histone modification landscape in fission yeast is almost identical to that in human cells. The research program has two broad objectives: 1.Determine how the histone modification landscape regulates gene expression. To do this, we will use detailed biochemical experiments to assess function of modified histones and an array of genetically modified yeast strains. 2.Determine the consequences of "aberrant" transcription for gene regulation. To do this, we will use techniques that allow us to monitor where aberrant transcription occurs throughout the genome. Through these studies, we will arrive at novel, fundamental insights into gene regulatory mechanisms that relate to histone modifications. We will also gain valuable knowledge into how defects in histone modification patterns can disrupt gene regulation.