SMARCB1 regulated SWI/SNF complex function in Malignant Rhabdoid Tumors

SMARCB1 在恶性横纹肌样肿瘤中调节 SWI/SNF 复合体功能

• 批准号: 10586154
• 负责人: Xiaofeng Wang
• 金额: $ 36.76万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586154
• 关键词: 3-Dimensional; Affect; Architecture; Award; Binding; Biochemical; Biological Assay; Biology; Catalogs; Child; Chromatin; Chromatin Remodeling Factor; Complex; Development; Enhancers; Epigenetic Process; Genetic Transcription; Genetically Engineered Mouse; Genomics; Goals; Heterogeneity; High-Throughput Nucleotide Sequencing; Higher Order Chromatin Structure; Histones; Human; Investigation; Label; Link; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Molecular; Mutate; Mutation; Names; Oncogenic; Prevalence; Proteins; Recurrence; Research; Research Proposals; Residual state; Rhabdoid Tumor; Role; SMARCB1 gene; SWI/SNF Family Complex; Series; Structure; Techniques; Technology; Testing; Tissues; Tumor Cell Line; Tumor Suppressor Proteins; Work; cancer genome; chromatin remodeling; cofactor; epigenome; epigenomics; experimental study; genome sequencing; genome-wide; infancy; innovation; insight; loss of function mutation; member; novel; programs; protein complex; protein protein interaction; transcription factor; transcriptome; tumor; tumorigenesis

PROJECT SUMMARY A research program will be undertaken to study SMARCB1-regulated SWI/SNF complex function in malignant rhabdoid tumors. Over the past few years, major cancer genome sequencing studies have identified frequent inactivating mutations of mammalian SWI/SNF chromatin remodeling complex in over 25% of human cancers. Despite the prevalence of SWI/SNF mutations, the contributions of these alterations to tumorigenesis remain unclear. SMARCB1, a core subunit of the complex, was the first subunit linked to cancer when it was found to be recurrently mutated in almost all cases of malignant rhabdoid tumors (RT). While studies using genetically engineered mouse models have firmly established SMARCB1 as a tumor suppressor, the epigenetic mechanism by which SMARCB1 mutation drives tumorigenesis remains elusive. The central hypothesis is that the biochemical diversity of the SWI/SNF complex composition determines its function in proper chromatin targeting to maintain discrete chromatin landscapes and transcriptional programs. Mutation of SMARCB1 leads to aberrant intra- and inter-complex protein-protein interactions that influence chromatin targeting, which consequently alters chromatin landscapes and higher-order structures, and promote an oncogenic epigenome and transcriptome. The objective is to determine the role of SMARCB1 in SWI/SNF subcomplex formation and the impact of these dynamics on chromatin targeting and higher-order chromatin structure. Our ultimate goal is to determine the fundamental epigenetic mechanism(s) by which loss of this chromatin regulatory subunit drives rhabdoid tumor development. To test this hypothesis, we will use a combination of cutting edge biochemical, molecular, and high-throughput sequencing technologies to move forward the program through the following specific aims: Aim 1, Determine SMARCB1 regulated SWI/SNF subcomplex assembly dynamics and identify SWI/SNF interactome in rhabdoid tumors; Aim 2, Determine the chromatin targeting activities of SWI/SNF subcomplexes and their relationship with other epigenetic regulators in rhabdoid tumors; Aim 3, Define higher- order chromatin structures regulated by the SWI/SNF complex in rhabdoid tumors.

项目摘要 将进行研究计划，以研究恶性肿瘤的SMARCB1调节的SWI/SNF复合功能 色鹿肿瘤。在过去的几年中，主要的癌症基因组测序研究已经确定 超过25％的人类癌症中哺乳动物SWI/SNF染色质重塑复合物的灭活突变。 尽管SWI/SNF突变的流行率，但这些改变对肿瘤的贡献仍然存在 不清楚。 SMARCB1是该综合体的核心亚基，是与癌症相关的第一个亚基。 在几乎所有恶性胸腺肿瘤（RT）的病例中，会反复突变。而研究使用遗传学 工程的小鼠模型已牢固地确立了SMARCB1作为肿瘤抑制剂，即表观遗传机制 Smarcb1突变驱动肿瘤发生仍然难以捉摸。中心假设是 SWI/SNF复合物的生化多样性决定其在适当染色质靶向的功能 维持离散的染色质景观和转录程序。 SMARCB1的突变导致 影响染色质靶向的异常内和复合体间蛋白 - 蛋白质相互作用，这 因此，改变了染色质景观和高阶结构，并促进致癌表观基因组 和转录组。目的是确定SMARCB1在SWI/SNF子复合形成中的作用 这些动力学对染色质靶向和高阶染色质结构的影响。我们的最终目标是 为了确定基本的表观遗传机制，该机制通过该染色质调节驱动器的损失 色鹿肿瘤的发展。为了检验这一假设，我们将使用最先进的生化的组合 分子和高通量测序技术，以通过以下 具体目的：目标1，确定SMARCB1受调节的SWI/SNF子复合组装动力学并识别 SWI/SNF相互作用在纹状体肿瘤中； AIM 2，确定SWI/SNF的染色质靶向活动 子复合物及其与其他表观遗传调节剂的关系； AIM 3，定义更高 在色粒肿瘤中由SWI/SNF复合物调控的秩序染色质结构。