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(和所有生物体)许多重要生物学功能的基础，包括细胞生长、细胞分裂和在发育过程中建立适当的细胞身份。基因是通过一个高度复杂的多步骤过程来启动的。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接触，并将其用作模板来制造信使RNA副本。这一过程被称为转录，在细胞中受到高度调控。为了正确地进行转录，染色体DNA需要能够被执行转录的蛋白质所访问，这需要改变和重新排列称为组蛋白的关键DNA包装蛋白质。有趣的是，组蛋白-DNA结构的组蛋白修饰和重排是执行转录的蛋白质机制所固有的一种能力。它使用的一个重要机制是组蛋白的化学修饰，这会改变它们的属性以促进转录。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高度保守，并且在每个基因上几乎是相同的。这表明该模式在转录过程中扮演着重要的角色，尽管定义这是什么一直是具有挑战性的。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，导致异常RNA的产生。这种模式是在用基因操纵的模式生物进行的实验中完成的。我们建议研究组蛋白修饰的转录“景观”。我们的研究将使用一种简单的模式生物--分裂酵母，它可以很容易地进行培养和遗传操作。重要的是，分裂酵母中的组蛋白修饰几乎与人类细胞中的完全相同。该研究计划有两个广泛的目标：1.确定组蛋白修饰环境如何调节基因表达。为此，我们将使用详细的生化实验来评估修饰的组蛋白和一系列转基因酵母菌株的功能。2.确定“异常”转录对基因调控的影响。为了做到这一点，我们将使用允许我们监测整个基因组中发生异常转录的位置的技术。通过这些研究，我们将获得与组蛋白修饰相关的基因调控机制的新的、基本的见解。我们还将获得有价值的知识，了解组蛋白修饰模式中的缺陷如何破坏基因调控。

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.