Epigenetic control of virulence in a fungal meningitis pathogen

真菌性脑膜炎病原体毒力的表观遗传控制

• 批准号: 9094454
• 负责人: Hiten D Madhani
• 金额: $ 38.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9094454
• 关键词: Accounting; Animals; Biological; Chromatin; Chromosomes; Complex; Cryptococcus; Cryptococcus neoformans; DNA; DNA Sequence; Deacetylase; Defect; Deposition; Development; Epigenetic Process; Event; Fission Yeast; Fungal Meningitis; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genome; Genotype; Goals; Health; Heterochromatin; Histone Deacetylase; Histone H3; Homologous Gene; Human; Investigation; Licensing; Lysine; Malignant Neoplasms; Mediating; Mediator of activation protein; Memory; Methylation; Methyltransferase; Modeling; Molecular; PRC1 Protein; Phenotype; Plants; Play; Polycomb; Property; Proteins; Reaction; Regulation; Reporting; Repression; Role; Signal Transduction; Site; System; Testing; Variant; Virulence; Work; base; biochemical tools; disorder control; epigenetic memory; fungus; insight; microbial; pathogen; research study

 DESCRIPTION (provided by applicant): We have discovered a Polycomb repressive complex, PRC2, in the fungal meningitis pathogen Cryptococcus neoformans, that silences chromatin domains via methylation of histone H3 on lysine 27 (H3K27me). This is the first Polycomb system to be identified in a human pathogen. We propose to define the core properties and components of this system and to investigate the role of H3K27me regulation in adaptation to the host. The Polycomb silencing systems of animals and plants are critical epigenetic regulators of development that, remarkably, mediate heritable memory of prior developmental and environmental events. Polycomb systems are composed of the PRC2 complex, which catalyzes H3K27me, and the PRC1 complex, which monoubiquitylates H2A and mediates chromatin compaction. Such chromatin is also designated facultative heterochromatin because it can be dynamically regulated. The genomes of a handful of other fungi have also been reported to encode predicted PRC2 components, raising the possibility that the system functions as a general epigenetic regulator in this kingdom. We purified the five-subunit PRC2-like complex of C. neoformans and showed that it mediates subtelomeric H3K27 trimethylation (H3K27me3) and gene silencing near chromosome ends. Our studies also revealed that a chromodomain subunit of the PRC2 complex directly recognizes the H3K27me3 product of the methyltransferase, thereby effectively tethering the PRC2-like complex to the sites of previous action. Our finding that the disruption of this tethering activity results in ectopic H3K27me3 deposition at H3K9me-marked sites of constitutive heterochromatin was unexpected and demonstrates the utility of the system for obtaining new insights. The powerful genetic and biochemical tools available in C. neoformans provide unique opportunities both to elucidate the fundamental properties of a Polycomb system and to investigate the biological role of H3K27me regulation in the adaptation of a pathogen to its mammalian host. To accomplish these goals we will 1) elucidate the core properties of PRC2-mediated gene regulation, 2) define the molecular components of the C. neoformans Polycomb system, and 3) investigate the role of Polycomb in the modulation of virulence. These experiments will elucidate inputs and epigenetic properties of this mechanism, the first Polycomb system to be uncovered in a human pathogen. Furthermore, the proposed work will identify new mediators of a fungal Polycomb system, illuminate its relationship with its animal and plant counterparts, and enable mechanistic investigations. Finally, these studies will elucidate the role of H3K27me regulation in pathogen adaptation to the host.

 描述（由申请人提供）：我们在真菌性脑膜炎病原体新型隐球菌中发现了一种 Polycomb 抑制复合物，PRC2，它通过赖氨酸 27 (H3K27me) 上的组蛋白 H3 甲基化来沉默染色质结构域。这是第一个被鉴定的 Polycomb 系统。我们建议定义该系统的核心特性和组成部分，并研究 H3K27me 的作用。动物和植物的 Polycomb 沉默系统是发育的关键表观遗传调节因子，它不常见地介导先前发育和环境事件的遗传记忆，由催化 H3K27me 的 PRC2 复合物和PRC1 复合体，单泛素化 H2A 并介导染色质压缩，这种染色质也被称为兼性异染色质，因为它可以动态变化。据报道，少数其他真菌的基因组也编码预测的 PRC2 成分，这提高了该系统在该领域作为通用表观遗传调节因子的可能性。并表明它介导亚端粒 H3K27 三甲基化 (H3K27me3) 和染色体末端附近的基因沉默。我们的研究还表明 PRC2 复合体的染色质结构域亚基直接识别。我们发现这种束缚活性的破坏导致 H3K27me3 异位沉积在组成型异染色质的 H3K9me 标记位点，从而有效地束缚 PRC2 样复合物，这证明了其效用。新型隐球菌中可用的强大遗传和生化工具为获得新见解的系统提供了独特的机会。阐明 Polycomb 系统的基本特性，并研究 H3K27me 调节在病原体适应哺乳动物宿主中的生物学作用。为了实现这些目标，我们将 1) 阐明 PRC2 介导的基因调节的核心特性，2) 定义。新型隐球菌 Polycomb 系统的分子成分，以及 3) 研究 Polycomb 在毒力调节中的作用这些实验将阐明该机制的输入和表观遗传特性，此外，拟议的工作将确定真菌 Polycomb 系统的新介质，阐明其与动物和植物人员的关系，并进行机制研究，最后，这些研究将阐明其作用。 H3K27me 在病原体适应宿主过程中的调控。