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(申请人提供)：我们在真菌脑膜炎病原体新生隐球菌中发现了一种多梳抑制复合体PRC2，它通过组蛋白H3在赖氨酸27(H3K27me)上的甲基化来沉默染色质结构域。这是第一个在人类病原体中发现的聚梳系统。我们建议定义该系统的核心属性和组件，并研究H3K27me调控在适应宿主中的作用。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，显著地调节对先前发育和环境事件的可遗传记忆。多梳系统由催化H3K27Me的PRC2复合体和催化H2A并介导染色质紧致的PRC1复合体组成。这种染色质也被称为兼性异染色质，因为它可以动态调节。据报道，其他一些真菌的基因组也编码了预测的PrC2成分，这增加了该系统在这个王国作为一般表观遗传调节因子发挥作用的可能性。我们纯化了新生隐孢子虫的5个亚基类似PrC2的复合体，并表明它介导了亚端粒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复合体的一个铬结构域亚单位直接识别甲基转移酶的H3K27me3产物，从而有效地将PRC2样复合体与先前作用的位点捆绑在一起。我们的发现是意想不到的，这种拴系活动的中断导致了H3K27me3在H3K9me标记的成分异染色质位点的异位沉积，并证明了该系统在获得新见解方面的实用性。新生弧菌强大的遗传和生化工具为阐明多梳系统的基本性质和研究H3K27me调控在病原体适应哺乳动物宿主中的生物学作用提供了独特的机会。为了实现这些目标，我们将1)阐明PrC2介导的基因调控的核心特性，2)定义新生葡萄球菌Polycomb系统的分子组成，3)研究Polycomb在毒力调节中的作用。这些实验将阐明这一机制的输入和表观遗传学特性，这是在人类病原体中发现的第一个多梳系统。此外，拟议的工作将确定真菌聚簇系统的新介体，阐明其与动植物对应物的关系，并使机械调查成为可能。最后，这些研究将阐明H3K27me调控在病原菌适应宿主中的作用。