Investigating essential chromatin regulators in cancers with SWI/SNF mutations

研究具有 SWI/SNF 突变的癌症中的必需染色质调节因子

• 批准号: 10607451
• 负责人: Hayden Abigail Malone
• 金额: $ 4.37万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607451
• 关键词: Ablation; Acetylation; Acetyltransferase; Address; Adult; Alleles; Automobile Driving; Binding; Binding Proteins; Biochemical; Biology; CRISPR screen; Cancer Etiology; Cancer cell line; Cells; Chemicals; Child; Childhood; Chromatin; Chromatin Remodeling Factor; Complex; Data; Dependence; Diploidy; Disease; Enhancers; Gene Expression; Genes; Genetic Transcription; Germ-Line Mutation; Goals; Histone Acetylation; Histones; Infant; Lysine; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Mentors; Mitosis; Mutate; Mutation; Neurodevelopmental Disorder; Nucleosomes; Outcome; PH Domain; Post-Translational Protein Processing; Prognosis; Proteins; Publishing; Reader; Regulation; Reporting; Rhabdoid Tumor; Role; SMARCB1 gene; SWI/SNF Family Complex; Site; Soft Tissue Neoplasms; Study models; Training; Transcriptional Regulation; Tumor Cell Line; Writing; cancer genome; design; experimental study; genome-wide; inhibitor; insight; member; mutant; neoplastic cell; new therapeutic target; novel; overexpression; pharmacologic; preservation; promoter; recruit; scaffold; therapeutic target; ubiquitin ligase

PROJECT SUMMARY Genes that encode subunits of SWI/SNF chromatin remodeling complexes are mutated in nearly 25% of cancers. Additionally, germline mutations in SWI/SNF subunits cause several neurodevelopmental disorders. However, the mechanisms by which these mutations drive cancer and disease are poorly understood. SWI/SNF complexes mobilize nucleosomes at enhancers and promoters to modulate transcription. Biallelic inactivation of SMARCB1, a gene encoding a SWI/SNF complex subunit, causes pediatric rhabdoid tumors (RTs). These highly aggressive soft tissue tumors occur in infants and young children and have extremely poor outcomes. Since RT genomes are diploid and lack other mutations, they are ideal for studying SWI/SNF-specific mechanisms driving cancer and for identifying novel therapeutic targets. My mentor and his collaborators initiated the Pediatric Cancer Dependency Project to identify novel drivers and therapeutic targets in pediatric cancers, including RT. Performing genome-wide CRISPR screens in 10 RT cell lines compared to over 800 other cancer cell lines revealed a novel gene that SMARCB1-deficient RT specifically depend upon for survival. This proposal seeks to investigate the function of this putative chromatin regulator and to determine why it constitutes a specific dependency in RT. Overexpression of this gene is associated with poor prognosis in several cancers and thus pharmacological efforts are already underway to develop chemical inhibitors. Intriguingly, preliminary experiments suggest that this protein may control histone post-translational modifications (PTMs) that dictate remodeling by SWI/SNF complexes and gene expression. Understanding why RT cells depend on this protein for survival will reveal novel mechanisms of chromatin regulation and may identify a new therapeutic target in these lethal cancers. My central hypothesis is that this protein controls histone PTMs and is required for the chromatin recruitment of the sole family of SWI/SNF complexes that lack SMARCB1, thus making it essential in RT. This proposal will investigate how this regulator, which lacks enzymatic activity, controls these histone PTMs and how this influences chromatin accessibility. Additionally, it will determine how this regulator influences remodeling and gene expression controlled by SWI/SNF complexes. Collectively, this proposal will uncover the function of this relatively understudied protein, provide novel insight into how chromatin function is regulated, explain why RTs selectively depend on this protein for survival, and potentially identify a novel therapeutic target in the lethal pediatric rhabdoid tumor. Additionally, this proposal is designed to address my training goal of becoming proficient in studying chromatin biology both experimentally and computationally.

项目摘要 在近25％的癌症中，将编码SWI/SNF染色质重塑复合物的亚基的基因突变。 此外，SWI/SNF亚基中的种系突变引起了几种神经发育障碍。然而， 这些突变驱动癌症和疾病的机制知之甚少。 SWI/SNF 复合物在增强子和启动子处动员核小体调节转录。双重失活 SMARCB1是编码SWI/SNF复合物亚基的基因，会导致小儿胸腺肿瘤（RTS）。这些很高 侵略性软组织肿瘤发生在婴儿和幼儿中，结果极差。自RT 基因组是二倍体，缺乏其他突变，它们非常适合研究SWI/SNF特异性机制 癌症和确定新型治疗靶标。我的导师和他的合作者发起了儿科 癌症依赖性项目，以识别包括RT在内的小儿癌症中的新驱动因素和治疗靶标。 与其他800多个其他癌细胞系相比，在10个RT细胞系中进行全基因组CRISPR筛选 揭示了一个新的基因，即缺乏缺陷的RT专门依靠生存。该建议寻求 研究该推定的染色质调节剂的功能，并确定为什么它构成A RT中的特定依赖性。该基因的过表达与几种癌症的预后不良有关 因此，已经正在进行制定化学抑制剂的药理努力。有趣的是，初步 实验表明该蛋白可能控制组蛋白后翻译后修饰（PTMS） 通过SWI/SNF复合物和基因表达进行重塑。了解为什么RT细胞取决于该蛋白 为了生存，将揭示染色质调节的新型机制，并可能确定一个新的治疗靶标 这些致命的癌症。我的中心假设是该蛋白控制组蛋白PTM，是必需的 缺乏SMARCB1的SWI/SNF综合体唯一的染色质募集，从而使其成为 在RT中必不可少。该提议将调查该调节器如何缺乏酶活性，它如何控制这些调节器 组蛋白PTM及其如何影响染色质的可及性。此外，它将决定该调节器如何 影响由SWI/SNF复合物控制的重塑和基因表达。总的来说，该提议将 发现这种相对研究的蛋白质的功能，提供了有关染色质功能的新洞察力 受调节，解释为什么RT选择性地依靠该蛋白质来生存，并有可能识别一种新颖的 致命的小儿胸腺肿瘤中的治疗靶标。此外，该建议旨在解决我的 培训目标是在实验和计算上熟练研究染色质生物学。