Inheritance of histone post-translational modifications

组蛋白翻译后修饰的遗传

• 批准号: RGPIN-2018-04907
• 负责人: Howe, LeAnn
• 金额: $ 7.29万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744259
• 关键词: Inheritance; histone; post; translational; modifications

Multicellular organisms are comprised of different cell types that share the same genome. Cell identity is therefore dictated by the subset of genes that are transcribed in each cell type. Factors that regulate gene expression can be divided into two classes: those that maintain genes in an “ON” state and those that maintain genes in an “OFF” state. The major question in the field of gene regulation is how these proteins maintain transcription patterns in replicating cells, when genome duplication requires unwinding of DNA strands and disruption of associated proteins.Eukaryotic DNA is packaged with a conserved class of proteins, known as histones. Histones are post-translationally modified by enzymes known as "writers", and different post-translational modifications (PTMs) are associated with gene activation and repression. Histone PTMs hold much promise as heritable markers of gene expression states. Histones displaced during DNA replication are deposited close to their original location on nascent DNA. Genetic studies in yeasts and Drosophila have identified numerous writer enzymes that play roles in inheritance of gene expression states. Despite this evidence however, we have failed to determine whether survival of histone PTMs following genome duplication is a general phenomenon. Instead, many studies have shown that histone PTMs are lost during DNA replication due to the presence of “eraser” enzymes, which remove histone PTMs. Interestingly, eraser enzymes may not be ubiquitously present and data exist demonstrating that the activity of erasers is regulated by the environment. The broad goal of our proposed research is to determine whether histone PTMs are heritable and under what conditions. To achieve our goal we will: 1) confirm that active histone PTMs are heritable genome-wide, 2) determine whether alteration of eraser activity by the environment affects inheritance of histone PTMs and 3) test whether histone PTMs regulate re-establishment of transcription patterns following DNA replication. We will use S. cerevisiae as a model organism because histones, writers, and erasers are conserved from yeasts to humans and because the experiments we propose would be extremely difficult and expensive to conduct in mammalian cells. Significance: Epigenetics refers to the inheritance of gene expression states without alteration of underlying DNA sequence. The epigenetic regulation of DNA-dependent processes has been intensely studied over the last two decades. However, despite the great interest in epigenetic inheritance, the underlying mechanisms involved remain largely unknown. The research described in this proposal will determine whether histone PTMs can and do mediate epigenetic inheritance and will help prepare seven higher-education students for successful careers in research.

多细胞生物体由共享相同基因组的不同细胞类型组成，因此细胞身份由每种细胞类型中转录的基因子集决定。调节基因表达的因素可分为两类：在同一细胞中维持基因的因素。 “ON”状态和那些维持基因处于“OFF”状态的基因调控领域的主要问题是，当基因组复制需要解开 DNA 链并破坏相关蛋白质时，这些蛋白质如何维持复制细胞中的转录模式。真核生物的DNA是组蛋白由一类保守的蛋白质（称为组蛋白）包装，由称为“作家”的酶进行翻译后修饰，并且不同的翻译后修饰 (PTM) 与基因激活和抑制相关。 DNA 复制过程中被替换的组蛋白沉积在靠近其原始位置的酵母和果蝇中。然而，尽管有这些证据，我们仍无法确定基因组复制后组蛋白 PTM 的存活是否是一种普遍现象，相反，许多研究表明，由于“橡皮擦”的存在，组蛋白 PTM 会在 DNA 复制过程中丢失。 ” 消除组蛋白 PTM 的酶暗示，擦除酶可能并不普遍存在，并且存在数据表明擦除酶的活性受环境调节。为了实现我们的目标，我们将：1) 确认活性组蛋白 PTM 在全基因组范围内是可遗传的，2) 确定环境对擦除活​​性的改变是否会影响组蛋白 PTM 的遗传，以及 3) 测试组蛋白 PTM 是否具有遗传性。我们将使用酿酒酵母作为模式生物，因为组蛋白、书写器和擦除器从酵母到人类都是保守的，并且因为我们提出的实验。意义：表观遗传学是指在不改变潜在 DNA 序列的情况下遗传基因表达状态。在过去的二十年里，人们对 DNA 依赖性过程的表观遗传调控进行了深入的研究。尽管人们对表观遗传非常感兴趣，但所涉及的潜在机制在很大程度上仍然未知，该提案中描述的研究将确定组蛋白 PTM 是否能够并且确实介导表观遗传，并将帮助七名高等教育学生为成功的研究生涯做好准备。