SMARCB1 regulated SWI/SNF complex function in Malignant Rhabdoid Tumors

项目摘要 将进行一项研究计划，研究SMARCB 1调节的SWI/SNF复合物在恶性肿瘤中的功能。 横纹肌样瘤在过去的几年里，主要的癌症基因组测序研究已经发现了频繁的 在超过25%的人类癌症中，哺乳动物SWI/SNF染色质重塑复合物的失活突变。 尽管SWI/SNF突变普遍存在，但这些改变对肿瘤发生的贡献仍然存在。 不清楚SMARCB 1是该复合物的核心亚基，当它被发现与癌症相关时，它是第一个与癌症相关的亚基。 在几乎所有的恶性横纹肌样瘤（RT）病例中均复发突变。虽然使用基因的研究 工程小鼠模型已经牢固地建立了SMARCB 1作为肿瘤抑制因子，表观遗传机制 SMARCB 1突变驱动肿瘤发生的机制仍然是难以捉摸的。核心假设是， SWI/SNF复合物组成的生物化学多样性决定了其在正确的染色质靶向中的功能 以维持离散的染色质景观和转录程序。SMARCB 1突变导致 影响染色质靶向的异常复合物内和复合物间蛋白质-蛋白质相互作用， 从而改变染色质景观和更高级的结构，并促进致癌表观基因组 和转录组。目的是确定SMARCB 1在SWI/SNF亚复合体形成中的作用， 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，通过该染色质调节亚基的丢失来驱动 横纹肌样瘤发展。为了验证这一假设，我们将使用最先进的生物化学， 分子和高通量测序技术，通过以下方式推进该计划 具体目标：目标1，确定SMARCB 1调节的SWI/SNF亚复合物组装动力学，并鉴定 横纹肌样瘤中SWI/SNF相互作用组的研究目的2：确定SWI/SNF的染色质靶向活性 横纹肌样瘤中的亚复合物及其与其他表观遗传调节因子的关系;目的3，定义更高- 横纹肌样瘤中SWI/SNF复合物调控的染色质结构顺序。

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.