Genome Architecture in Human Germinal Center B Cell Development, Malignancy, and Somatic Hypermutation

人类生发中心 B 细胞发育、恶性肿瘤和体细胞超突变中的基因组结构

基本信息

批准号：
10478178
负责人：
David G. Schatz
金额：
$ 64.07万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478178
关键词：
3-Dimensional Address Affect Antibodies Antibody Affinity Antibody-mediated protection Architecture B-Cell Development B-Cell Lymphomas B-Lymphocyte Subsets B-Lymphocytes Biology Cell Line Cell Lineage Cells Chromatin Chromatin Loop Chromosomal translocation Chromosomes Complex DNA DNA Folding Development Elements Environment Exhibits Future Generations Genes Genetic Transcription Genome Genomic Instability Genomic Segment Genomics Human Image Imaging technology Immune response Immunobiology Immunoglobulin Genes Immunoglobulin Somatic Hypermutation Immunoglobulins Immunooncology In Situ Individual Investigation Lead Length Link Lymphoma Lymphoma cell Malignant - descriptor Malignant Neoplasms Mammalian Cell Methods Mutate Mutation Normal Cell Nuclear Nuclear Lamina Nuclear Pore Nuclear Pore Complex Oncogenic Organelles Phase Point Mutation Positioning Attribute Predisposition Process Property RNA Research Resistance Resolution Role Sampling Site Structure Structure of germinal center of lymph node Techniques Testing Three-dimensional analysis Tissue Sample Tissues Tonsil Vaccines Work cancer cell cell type cohesion human tissue insight multiplexed imaging novel imaging technology novel strategies pathogen programs single molecule tumorigenesis

项目摘要

SUMMARY During the humoral immune response, somatic hypermutation (SHM) introduces point mutations in rearranged immunoglobulin (Ig) genes of activated germinal center (GC) B cells. SHM is essential for the fine-tuning of antibody affinity, the generation of B cells expressing high-affinity antibody, and the efficacy of many vaccines. Mistargeted SHM activities can lead to mutations and chromosomal translocations that contribute to the development of B cell lymphoma. Recent studies suggest that the three-dimensional (3D) organization of the genome regulates SHM targeting and mistargeting. However, it is largely unknown how the genome is spatially organized across multiple length scales in GC B cell development and lymphoma, and how 3D genome architecture mechanistically affects the targeting and mistargeting of SHM. Conventional approaches cannot address these questions in the primary GC tissue environment due to technical limitations. Here, we propose to apply a new method recently developed by our team, termed Multiplexed Imaging of Nucleome Architectures (MINA), to primary human tonsil tissue samples and malignant GC-derived human B cell lymphomas. We will investigate and test the association between SHM susceptibility and a variety of 3D nucleome architectures, including topologically associating domain (TAD) architecture, phase separation, and nuclear positioning of genomic regions relative to nuclear lamina, nucleoli, and nuclear pores. Through targeted genomic perturbations in human B cell lymphomas, we will test specific hypotheses linking SHM targeting elements to elevated chromatin looping interactions, TAD phase separation, nuclear pore proximity, and mutation vulnerability. Our study will significantly advance our understanding of the role of 3D genome architecture and nuclear organization in GC B cells undergoing SHM in both the developmental and tumorigenesis contexts. We expect this study to establish a new research paradigm and transform 3D nucleome investigations in immunobiology.

概括在体液免疫反应期间，躯体超成名（SHM）引入了点突变活化生发中心（GC）B细胞的重新排列免疫球蛋白（IG）基因。 SHM对于抗体亲和力的微调，表达高亲和力抗体的B细胞的产生以及许多疫苗。被误入的SHM活动会导致突变和染色体易位有助于B细胞淋巴瘤的发展。最近的研究表明三维（3D）基因组的组织调节SHM的靶向和误解。但是，这在很大程度上未知该基因组在GC B细胞发育和淋巴瘤中的多个长度尺度上进行空间组织，以及3D基因组架构如何机械地影响SHM的靶向和误解。传统方法无法在主要GC组织环境中解决这些问题技术限制。在这里，我们建议采用我们团队最近开发的新方法，称为核心体系结构（MINA）的多重成像，原发性扁桃体组织样品和恶性GC衍生的人B细胞淋巴瘤。我们将调查和测试SHM之间的关联敏感性和各种3D核心体系结构，包括拓扑结合域（TAD）基因组区域相对于核层的结构，相分离和核定位，核仁和核孔。通过人类B细胞淋巴瘤的靶向基因组扰动，我们将测试特定的假设，将SHM靶向元件与升高的染色质环相互作用联系起来，TAD 相分离，核孔的接近和突变脆弱性。我们的研究将大大推动我们的了解3D基因组结构和核组织在接受GC B细胞中的作用在发育和肿瘤发生环境中的SHM。我们希望这项研究能够建立一个新的研究范例和转化3D核心组研究中的3D核心研究。