SMARCB1 regulated SWI/SNF complex function in Malignant Rhabdoid Tumors

项目总结 将开展一项研究计划，以研究SMARCB1调节的SWI/SNF复合体在恶性肿瘤中的作用 横纹肌样瘤。在过去的几年里，主要的癌症基因组测序研究发现 在超过25%的人类癌症中，哺乳动物SWI/SNF染色质重塑复合体的失活突变。 尽管SWI/SNF突变普遍存在，但这些突变对肿瘤发生的贡献仍然存在 不清楚。SMARCB1是该复合体的一个核心亚单位，当它被发现时，是第一个与癌症有关的亚基 在几乎所有的恶性横纹肌样肿瘤(RT)中都有反复突变。虽然在研究中使用基因 基因工程小鼠模型已经牢固地确立了SMARCB1作为肿瘤抑制因子，即表观遗传机制 SMARCB1突变是如何驱动肿瘤发生的，目前仍不清楚。中心假设是 SWI/SNF复合体组成的生物化学多样性决定了其在适当的染色质靶向中的作用 以维持不连续的染色质景观和转录程序。SMARCB1基因突变导致 影响染色质靶向的复合体内和复合体间蛋白相互作用的异常 因此，改变染色质景观和高阶结构，促进致癌表观基因组 和转录组。目的是确定SMARCB1在SWI/SNF亚复合体形成中的作用以及 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 确定这个染色质调节亚基丢失驱动的基本表观遗传机制(S) 横纹肌样肿瘤的发展。为了验证这一假设，我们将使用尖端生物化学、 分子测序和高通量测序技术通过以下几个方面推进该计划 具体目标：目标1，确定SMARCB1调控的SWI/SNF亚复合体组装动力学并确定 SWI/SNF与横纹肌样肿瘤的相互作用；目的2，测定SWI/SNF的染色质靶向活性 横纹肌样肿瘤中的亚复合体及其与其他表观遗传调节因子的关系；目标3，定义更高的- 横纹肌样肿瘤中受SWI/SNF复合体调控的染色质有序结构。

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.