Defining the role of the BCL7 subunit of mammalian SWI/SNF chromatin remodeling complexes in human cancer

确定哺乳动物 SWI/SNF 染色质重塑复合物的 BCL7 亚基在人类癌症中的作用

• 批准号: 10450322
• 负责人: Kimberlee Hixon
• 金额: $ 4.05万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450322
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Affect; Amino Acids; Antibodies; Architecture; B cell differentiation; B-Cell Lymphomas; B-Lymphocytes; Binding; Biochemical; Biological Assay; Cell Differentiation process; Cell Line; Cell Maturation; Cell physiology; Cell surface; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Chronic Lymphocytic Leukemia; Combinatorics; Complex; Computer Analysis; DNA; Deletion Mutation; Development; Disease; Evolution; Family; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Genomic approach; Genomics; Human; Immune system; Immunoprecipitation; Infection; Knock-out; Length; Link; Lymphoma; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Mediating; Multiple Myeloma; Multiprotein Complexes; Mutate; Mutation; N-terminal; Neurodevelopmental Disorder; Nucleosomes; Oncogenic; Organism; Pathogenesis; Physiological Processes; Play; Process; Protein Subunits; Research; Role; SMARCA4 gene; SMARCC1 gene; Series; Site; Systems Development; Tissues; Transposase; Variant; Western Blotting; base; cancer subtypes; cell fate specification; chromatin immunoprecipitation; gene product; genome-wide; human disease; large cell Diffuse non-Hodgkin' s lymphoma; nuclease; programs; protein complex; transcriptome sequencing; tumorigenesis; vector control

PROJECT SUMMARY/ABSTRACT The mammalian SWI/SNF (mSWI/SNF) complexes represent a family of ATP-dependent chromatin remodeling complexes (CRCs) that play critical roles in the maintenance of chromatin accessibility and gene expression. Mammalian SWI/SNF complexes are combinatorically assembled from 29 different gene products to generate three distinct 11-15-subunit classes termed BAF, pBAF, and ncBAF complexes. Importantly, mSWI/SNF genes are mutated in over 20% of human cancers, underscoring their critical roles in oncogenesis. While biochemical, structural and genomics-based studies over the past several years have begun to define subunit-specific contributions to overall protein complex function, most subunit functions remain unassigned. BCL7 is a recently- discovered component of all three SWI/SNF complex classes. Despite other mSWI/SNF complex subunits being conserved throughout evolution, BCL7 has only recently emerged in higher-order organisms, suggesting it may be necessary for specialized organismal processes such as mammalian cell differentiation or immune system development. I aim to define the role of the BCL7 subunit in mSWI/SNF complex function in the human cell context. I hypothesize that BCL7 is required for a) SWI/SNF complex biochemical integrity; and b) for genome-wide SWI/SNF targeting and DNA accessibility generation in lymphoma and primary B cells. The role of the mammalian-specific BCL7 subunit in the biochemical composition, targeting, and activity of SWI/SNF complexes remains unknown. First, I aim to determine the impact of BCL7 deletion on SWI/SNF complex biochemical integrity (subunit assembly and stability) and to define the region of BCL7 required for its incorporation into SWI/SNF complexes. BCL7 mutations, including deletions and single-residue substitutions, have been identified primarily in lymphomas and myelomas, cancer subtypes that affect B cell maturation and function. Second, I aim to determine the impact of BCL7 perturbations on the SWI/SNF complex genomic targeting, DNA accessibility generation, and subsequent gene expression in B cell lymphomas such as DLBCL. Third, I aim to determine the functional impact and role of BCL7 in SWI/SNF complex genomic targeting and accessibility generation in healthy human primary B cells. This research will elucidate key features of BCL7-mediated SWI/SNF complex composition, chromatin localization, and resulting DNA accessibility, and gene expression programs in normal and malignant B cells. The mechanisms governing chromatin remodeling complex activities during basic cellular processes and in human disease remain incompletely understood, and with the highly frequent mutations in these processes observed in human cancers, this is a uniquely pertinent and high-impact priority for the field at-large.

项目总结/摘要 哺乳动物SWI/SNF（mSWI/SNF）复合物是一类ATP依赖的染色质重塑蛋白 在维持染色质可及性和基因表达中起关键作用的CRCs。 哺乳动物SWI/SNF复合物由29种不同的基因产物组合组装而成， 三种不同的11-15亚基类型，称为BAF、pBAF和ncBAF复合物。重要的是，mSWI/SNF基因 在超过20%的人类癌症中发生突变，强调了它们在肿瘤发生中的关键作用。虽然是生化的， 在过去的几年里，基于结构和基因组学的研究已经开始定义亚基特异性 尽管亚基对整个蛋白质复合物功能的贡献很大，但大多数亚基功能仍然未分配。BCL 7是一个最近- 发现了所有三个SWI/SNF复杂类的组成部分。尽管其他mSWI/SNF复合物亚基被 BCL 7在整个进化过程中都是保守的，直到最近才出现在高等生物中，这表明它可能 对于专门的生物过程如哺乳动物细胞分化或免疫系统是必需的 发展我的目的是确定BCL 7亚基在人类细胞中mSWI/SNF复合物功能中的作用。 上下文 我假设BCL 7是a）SWI/SNF复合物生物化学完整性和B）全基因组表达所必需的。 淋巴瘤和原代B细胞中SWI/SNF靶向和DNA可及性的产生。的作用 SWI/SNF复合物的生化组成、靶向和活性中的大肠杆菌特异性BCL 7亚基 仍然未知。首先，我的目的是确定BCL 7缺失对SWI/SNF复合物生化的影响， 完整性（亚基组装和稳定性），并确定将其掺入BCL 7所需的区域 SWI/SNF复合物。已经鉴定了BCL 7突变，包括缺失和单残基取代， 主要是淋巴瘤和骨髓瘤，影响B细胞成熟和功能的癌症亚型。第二，我瞄准 为了确定BCL 7扰动对SWI/SNF复合物基因组靶向、DNA可及性的影响， 产生和随后在B细胞淋巴瘤如DLBCL中的基因表达。第三，我的目标是确定 BCL 7在SWI/SNF复合物基因组靶向和可及性产生中的功能影响和作用 健康人原代B细胞。 本研究将阐明BCL 7介导的SWI/SNF复合物组成、染色质 定位，和产生的DNA可及性，以及正常和恶性B细胞中的基因表达程序。 染色质重塑复合物在基本细胞过程中的作用机制和在细胞内的表达 人类疾病仍然不完全了解，并在这些过程中的高频率突变， 在人类癌症中观察到，这对整个领域来说是一个独特的相关和高影响力的优先事项。