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.

项目摘要/摘要 哺乳动物的SWI/SNF(mSWI/SNF)复合体代表一类依赖于ATP的染色质重塑 在维持染色质可及性和基因表达方面发挥关键作用的复合体(CRC)。 哺乳动物的SWI/SNF复合体由29种不同的基因产物组合而成 三个不同的11-15亚基类别，称为BAF、pBAF和ncBAF复合体。重要的是，mSWI/SNF基因 在超过20%的人类癌症中发生突变，这突显了它们在肿瘤发生中的关键作用。在生物化学的同时， 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特定亚基 对整体蛋白质复合体功能的贡献，大多数亚基功能仍未分配。BCL7是最近推出的一款 发现了所有三个SWI/SNF复杂类的组件。尽管其他mSWI/SNF复合亚单位 BCL7在整个进化过程中都是保守的，直到最近才在高等生物体中出现，这表明它可能 是哺乳动物细胞分化或免疫系统等特殊生物过程所必需的 发展。我的目标是确定BCL7亚基在人类细胞中mSWI/SNF复合体功能中的作用 背景。 我推测BCL7是a)SWI/SNF复合体生化完整性所必需的；以及b)全基因组所必需的 淋巴瘤和原代B细胞中SWI/SNF靶向和DNA可及性生成。美国政府的角色 哺乳动物特异性BCL7亚基在SWI/SNF复合体的生化组成、靶向性和活性中的作用 仍然不为人知。首先，我的目标是确定BCL7缺失对SWI/SNF复合体生化的影响 完整性(亚基组装和稳定性)，并确定其整合所需的BCL7区域 SWI/SNF复合体。已经确定了bcl7突变，包括缺失和单残基替换 主要是淋巴瘤和骨髓瘤，这是一种影响B细胞成熟和功能的癌症亚型。第二，我的目标 为了确定BCL7扰动对SWI/SNF复合体基因组靶向、DNA可及性的影响 B细胞淋巴瘤(如DLBCL)的发生和随后的基因表达。第三，我的目标是确定 BCL7在SWI/SNF复合体基因组靶向和可及性生成中的功能影响和作用 健康人原代B细胞。 本研究将阐明BCL7介导的SWI/SNF复合体成分染色质的关键特征 在正常和恶性B细胞中的定位和由此产生的DNA可及性，以及基因表达程序。 染色质重塑复合体在基本细胞过程和细胞周期中的作用机制 人类疾病仍然没有完全被了解，并且在这些过程中频繁地发生突变 在人类癌症中观察到，对于整个领域来说，这是一个独特的相关和高影响的优先事项。