Investigating the functions of histone acetylation in genome organization and leukemogenesis

研究组蛋白乙酰化在基因组组织和白血病发生中的功能

• 批准号: EP/Y000331/1
• 负责人: Aliaksandra Radzisheuskaya
• 金额: $ 164.7万
• 依托单位: Institute of Cancer Research
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY000331%2F1
• 关键词: Investigating; functions; histone; acetylation; genome

Chromatin structure plays a central role in controlling cell phenotype. This is highlighted by altered epigenomes and frequent mutations in chromatin regulators in cancer cells. Despite recent advances in epigenetics, we currently lack detailed mechanistic understanding of how chromatin organization contributes to gene expression, genome stability and cancer initiation, which hinders development of efficient therapies. Acetylation of histone proteins is considered to facilitate local DNA access for regulators of genomic processes such as transcription, replication, and repair. Acetylation of histone H3 on lysine 23 (H3K23ac) stands out among other acetylation sites due its high abundance in mammalian chromatin, which challenges the generally assumed local DNA accessibility role and instead suggests a function in more global processes of genome organization. Knockouts of the enzymes placing H3K23ac, KAT6A and KAT6B, have strong developmental phenotypes. Moreover, chromosomal translocations generating KAT6A- or KAT6B-containing fusion proteins induce acute myeloid leukemia. Together, these observations indicate an important yet unexplored role of H3K23ac in regulating cell phenotype. I hypothesize that H3K23ac confers a specific chromatin structure that ensures correct genomic organisation and which misregulation induces leukemia. To investigate this, I will develop novel cell and mouse models and will use a combination of cutting-edge genetic, genomic and cell biology approaches to investigate the role of H3K23ac in normal and leukemic cells. In addition, I will establish several key methodologies (chromatin environment profiling and histone gene mutagenesis) that will transform the way histone modifications are investigated in mammals. In the long-term, the proposed work will serve as a strong conceptual and methodological foundation to answer the fundamental questions of how chromatin structure and function influence cell phenotype and induce disease.

染色质结构在控制细胞表型中起着核心作用。这突出表现在改变的表观基因组和癌细胞中染色质调节因子的频繁突变。尽管最近在表观遗传学方面取得了进展，但我们目前缺乏对染色质组织如何促进基因表达、基因组稳定性和癌症起始的详细机制理解，这阻碍了有效疗法的开发。组蛋白的乙酰化被认为有助于基因组过程（如转录、复制和修复）的调节因子进入局部DNA。组蛋白H3在赖氨酸23（H3K23ac）上的乙酰化由于其在哺乳动物染色质中的高丰度而在其他乙酰化位点中脱颖而出，这挑战了通常假设的局部DNA可及性作用，而是表明在基因组组织的更全局过程中的功能。酶H3K23ac、KAT6A和KAT6B的敲除具有强的发育表型。此外，产生含KAT6A或KAT6B的融合蛋白的染色体易位诱导急性髓性白血病。总之，这些观察结果表明H3K23ac在调节细胞表型中的重要但未探索的作用。我假设H3K23ac赋予了一种特定的染色质结构，以确保正确的基因组组织，而这种错误调节会诱导白血病。为了研究这一点，我将开发新的细胞和小鼠模型，并将使用尖端的遗传学，基因组学和细胞生物学方法的组合来研究H3K23ac在正常和白血病细胞中的作用。此外，我将建立几个关键的方法（染色质环境分析和组蛋白基因诱变），这将改变组蛋白修饰的方式在哺乳动物中进行调查。从长远来看，拟议的工作将作为一个强大的概念和方法基础，以回答染色质结构和功能如何影响细胞表型和诱导疾病的基本问题。