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: 10604291
• 负责人: Kimberlee Hixon
• 金额: $ 4.14万
• 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/10604291
• 关键词: ATAC-seq; 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; Chromatin; Chromatin Remodeling Factor; Chronic Lymphocytic Leukemia; Combinatorics; Complex; Computer Analysis; DNA; Dedications; 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; Proliferating; Protein Subunits; Research; Role; SMARCA4 gene; SMARCC1 gene; SWI/SNF Family Complex; Series; Site; Systems Development; Tissues; Transposase; Variant; Western Blotting; 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; vector control; ATAC-seq; 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; Chromatin; Chromatin Remodeling Factor; Chronic Lymphocytic Leukemia; Combinatorics; Complex; Computer Analysis; DNA; Dedications; 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; Proliferating; Protein Subunits; Research; Role; SMARCA4 gene; SMARCC1 gene; SWI/SNF Family Complex; Series; Site; Systems Development; Tissues; Transposase; Variant; Western Blotting; 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; 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.

项目摘要/摘要 哺乳动物SWI/SNF（MSWI/SNF）复合物代表ATP依赖性染色质重塑的家族 在维持染色质访问性和基因表达中起关键作用的复合物（CRC）。 哺乳动物SWI/SNF复合物是由29种不同基因产物组合组合的 三个不同的11-15个纯净类称为BAF，PBAF和NCBAF复合物。重要的是，MSWI/SNF基因 在超过20％的人类癌症中突变，强调了它们在肿瘤发生中的关键作用。虽然生化，但 在过去的几年中，基于结构和基因组学的研究已经开始定义亚基特异性 对整体蛋白质复合功能的贡献，大多数亚基功能仍然没有分配。 Bcl7是最近的 发现了所有三个SWI/SNF复合体类的组件。尽管其他MSWI/SNF复杂亚基是 在整个进化过程中保守，BCL7直到最近才出现在高阶生物中，这表明它可能 对于专门的有机过程（例如哺乳动物细胞分化或免疫系统）是必需的 发展。我的目的是定义Bcl7亚基在人体细胞中MSWI/SNF复合功能中的作用 语境。 我假设a）SWI/SNF复合物生化完整性所必需的BCl7； b）全基因组 淋巴瘤和原代B细胞中的SWI/SNF靶向和DNA可及性产生。角色 SWI/SNF复合物的生化组成，靶向和活性中的哺乳动物特异性BCl7亚基 仍然未知。首先，我的目的是确定Bcl7删除对SWI/SNF复合物生化的影响 完整性（亚基组装和稳定性），并定义将其掺入中所需的Bcl7区域 SWI/SNF复合体。已经确定 主要在淋巴瘤和骨髓瘤中，影响B细胞成熟和功能的癌症亚型。第二，我瞄准 为了确定BCl7扰动对SWI/SNF复合物基因组靶向的影响，DNA可及性 B细胞淋巴瘤（例如DLBCL）的产生和随后的基因表达。第三，我的目的是确定 BCl7在SWI/SNF复合物基因组靶向和可访问性中产生的功能影响和作用 健康的人类原代B细胞。 这项研究将阐明Bcl7介导的SWI/SNF复合物组成的关键特征，染色质 在正常和恶性B细胞中的定位，以及由此产生的DNA可及性以及基因表达程序。 在基本的蜂窝过程和中 人类疾病仍然不完全理解，并且在这些过程中的突变高度频繁 在人类癌症中观察到，这是该领域的独特相关和高影响力的优先级。