Dissecting the molecular mechanisms of PRC2 dysregulation in cancer

剖析癌症中 PRC2 失调的分子机制

• 批准号: 10805548
• 负责人: Agata Ewa Patriotis
• 金额: $ 8.94万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10805548
• 关键词: Address; Advanced Malignant Neoplasm; Allosteric Regulation; Architecture; Award; B-Cell Lymphomas; Binding; Biochemistry; Cancer Biology; Cancer Model; Catalysis; Cell Communication; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Clonal Evolution; Complex; Coupled; Data; Development; Drug resistance; EZH2 gene; Ectoderm; Embryo; Epigenetic Process; Focus Groups; Gene Expression; Gene Mutation; Genes; Genetic Screening; Genomics; Goals; Heterochromatin; Heterogeneity; Histone H3; Histones; Human; In Vitro; Lymphoma; Lysine; Maintenance; Malignant - descriptor; Malignant Neoplasms; Methylation; Microscopy; Modeling; Modification; Molecular; Molecular Biology; Mutate; Mutation; N-terminal; Neoplasms; Neoplastic Processes; Neurofibrosarcoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenocopy; Polycomb; Post-Translational Protein Processing; Postdoctoral Fellow; Process; Proliferating; Radiation therapy; Regulation; Research; Resistance; Role; Somatic Mutation; System; Technical Expertise; Techniques; Technology; Therapeutic; Therapeutic Intervention; Work; cancer cell; cancer prevention; cancer therapy; chemotherapy; drug resistance development; epigenetic regulation; epigenomics; experience; gain of function; gain of function mutation; genome-wide; genotoxicity; in vivo; insight; large cell Diffuse non-Hodgkin' s lymphoma; loss of function; loss of function mutation; malignant state; mutant; novel; novel strategies; preclinical development; programs; reconstitution; shift work; transcriptomics; tumor

Project Summary/Abstract The chromatin landscape governs basic cellular functions that are altered in cancer, including genomic architecture, gene expression, and developmental pathways. Interestingly, epigenetic dysregulation of chromatin is an emerging hallmark of cancer. These epigenetic changes in turn render cancer cells highly reliant on the chromatin machinery to maintain their malignant state, thus creating opportunities for therapeutic intervention by targeting chromatin modifiers. Driven by the desire to understand the basic mechanistic underpinnings of epigenetic regulation, it is my goal to address pressing questions in molecular biology and contribute to the advancement of cancer prevention and treatment. Histone post-translational modifications (PTMs) are central regulators of chromatin processes, and genes encoding chromatin factors are highly mutated in a range of cancers. This project seeks to understand the role of the Polycomb Repressive Complex 2 (PRC2) in cancer development. PRC2 is a major epigenetic machinery responsible for the maintenance of heterochromatin and catalysis of histone H3 lysine 27 methylation. The F99 phase of this proposal is focused on investigating the regulation of PRC2 enzymatic activity by the highly conserved SANT1-like binding (SBD) domain of its EZH2 subunit. Despite the broad understanding of PRC2 function and regulation, the molecular role of the N-terminal SBD of EZH2 is unknown. The preliminary data reveals novel mechanistic insight about this domain in the catalysis of H3K27 methylation. Surprisingly, partial deletion of the SBD domain in EZH2 (SBD-EZH2) leads to a global loss of repressive H3K27me2 and H3K27me3, phenocopying the complete loss of EZH2 at the epigenomic level. In the remainder of the dissertation work, my main research efforts will be directed toward delineating the regulatory significance of the EZH2-SBD domain in the allosteric activation of PRC2 enzymatic activity, as well as determining a potential inhibitory mechanism for lymphoma patients harboring EZH2 gain-of-function mutations. The K00 phase of this project will be focused on studying the role of PRC2 loss in the development of the highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). Interestingly, the loss of PRC2 components is involved in the malignant formation of sporadic and radiotherapy-associated MPNSTs. Thus, to further understand the molecular mechanisms of these tumors, I plan to expand my technical expertise to include high-throughput genetic screening, single-cell epigenomic and transcriptomic techniques, computational approaches, development of preclinical cancer models, and sequencing analysis of human tumor data. These new approaches, coupled with my already strong background in molecular biology, microscopy, and biochemistry, will allow me to address the most pressing and challenging issues in epigenetic regulation and cancer biology today. This award will allow to pursue the above questions and and gain experience in order to become a leader of my own cancer-focused group and a leader in the field of epigenetics.

项目概要/摘要 染色质景观控制癌症中改变的基本细胞功能，包括 基因组结构、基因表达和发育途径。 染色质是癌症的一个新兴标志，这些表观遗传变化反过来使癌细胞高度依赖。 染色质机制维持其恶性状态，从而为治疗创造机会 通过靶向染色质修饰剂进行干预由了解基本机制的愿望驱动。 作为表观遗传调控的基础，我的目标是解决分子生物学和 组蛋白翻译后修饰 (PTM) 是染色质过程的中央调节因子，编码染色质因子的基因高度突变 该项目旨在了解 Polycomb 抑制复合物 2 (PRC2) 的作用。 PRC2 是负责维持癌症发展的主要表观遗传机制。 异染色质和组蛋白 H3 赖氨酸 27 甲基化的催化。 该提案的 F99 阶段重点是研究 PRC2 酶活性的调节 尽管人们已经广泛了解，但其 EZH2 亚基的高度保守的 SANT1 样结合 (SBD) 结构域。 关于 PRC2 的功能和调节，EZH2 N 端 SBD 的分子作用尚不清楚。 初步数据揭示了该结构域在 H3K27 甲基化催化中的新机制。 令人惊讶的是，EZH2 (SBD-EZH2) 中 SBD 结构域的部分删除导致抑制性的整体丧失。 H3K27me2 和 H3K27me3，表观基因组水平上 EZH2 完全缺失。 在论文工作的其余部分，我的主要研究工作将集中于描绘监管 EZH2-SBD 结构域在 PRC2 酶活性变构激活中的重要性，以及 确定携带 EZH2 功能获得性突变的淋巴瘤患者的潜在抑制机制。 该项目的K00阶段将重点研究PRC2损失在开发中的作用 侵袭性高度恶性的周围神经鞘瘤（MPNST）。 成分参与散发性和放射治疗相关的 MPNST 的恶性形成。 进一步了解这些肿瘤的分子机制，我计划扩展我的技术专业知识，包括 高通量遗传筛选、单细胞表观基因组和转录组技术、计算 方法、临床前癌症模型的开发以及人类肿瘤数据的测序分析。 新的方法，加上我在分子生物学、显微镜学和 生物化学，将使我能够解决表观遗传调控中最紧迫和最具挑战性的问题 今天的癌症生物学将允许解决上述问题并获得经验，以便 成为我自己的癌症研究小组的领导者和表观遗传学领域的领导者。