Dissecting regulatory mechanisms governing histone H3 lysine 9 methylation

剖析组蛋白 H3 赖氨酸 9 甲基化的调控机制

• 批准号: BB/Y002857/1
• 负责人: Thomas Schalch
• 金额: $ 109.21万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY002857%2F1
• 关键词: Dissecting; regulatory; mechanisms; governing; histone

The genomes of eukaryotic organisms are covered by histone proteins, which act as a signalling platform that forms an integral part of the regulation and protection of the genome. The signals are post-translational modifications on histone tails for which there are "writer" and "eraser" enzymes as well as reader proteins that specifically bind the mark. This project focuses on an enzyme family called SUV39, which is at the heart of constitutive heterochromatin systems. We study proteins from human and fission yeast, a very informative model system for understanding the fundamental mechanisms of signalling on chromatin. SUV39 proteins deposit the histone H3 lysine 9 methyl marks (H3K9me), which are required to establish silent epigenetic states that can be propagated from one generation to the next without changes in the underlying DNA sequence. In mammals, SUV39 enzymes have been shown to be required for healthy development and their deregulation is associated with various cancers.Recent work in our and other laboratories has revealed that specific post-translational modifications, in particular ubiquitination on a residue close to H3K9, lysine 14, can stimulate the activity of the fission yeast SUV39 protein Clr4 on H3K9 by more than 250-fold. We have furthermore evidence, that phosphorylation on Clr4 itself regulates its H3K9 methyltransferase activity. This proposal is a collaborative effort that leverages our expertise in the high-resolution structural approaches of X-ray crystallography and NMR to visualize and understand how these post-translational modifications control SUV39 proteins. We will further determine by NMR the role of various structural states in the regulation of Clr4's activity. This rich understanding of SUV39 proteins will be beneficial to driving efforts forward to develop therapeutic approaches in cancer.

真核生物的基因组被组蛋白覆盖，组蛋白作为信号平台，构成了基因组调节和保护的组成部分。这些信号是组蛋白尾部的翻译后修饰，其中有“写入”酶和“擦除”酶以及特异性结合标记的读取蛋白。这个项目的重点是一个叫做SUV39的酶家族，它是构成异染色质系统的核心。我们研究来自人类和裂变酵母的蛋白质，这是一个非常有用的模型系统，用于理解染色质信号传导的基本机制。SUV39蛋白沉积组蛋白H3赖氨酸9甲基标记（H3K9me），这是建立沉默的表观遗传状态所必需的，这种状态可以在不改变基础DNA序列的情况下从一代传播到下一代。在哺乳动物中，SUV39酶已被证明是健康发育所必需的，其失调与各种癌症有关。我们和其他实验室最近的工作表明，特定的翻译后修饰，特别是靠近H3K9的残基赖氨酸14的泛素化，可以刺激H3K9上的裂变酵母SUV39蛋白Clr4的活性超过250倍。我们有进一步的证据表明，Clr4本身的磷酸化调节其H3K9甲基转移酶的活性。该提案是一项合作努力，利用我们在x射线晶体学和核磁共振的高分辨率结构方法方面的专业知识来可视化和理解这些翻译后修饰如何控制SUV39蛋白。我们将通过核磁共振进一步确定各种结构状态在Clr4活性调节中的作用。对SUV39蛋白的丰富理解将有助于推动癌症治疗方法的发展。