Chromunities Drive Transcriptional Reprogramming in Humoral Immunity and B-cell Lymphomas

染色体驱动体液免疫和 B 细胞淋巴瘤中的转录重编程

• 批准号: 10606730
• 负责人: Ceyda Durmaz
• 金额: $ 4.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2026-09-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606730
• 关键词: 3-Dimensional; Affect; Affinity; Architecture; Automobile Driving; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; BCL6 gene; Binding; Binding Sites; Biological; Biological Assay; Cell Maturation; Cells; Chromatin; Chromatin Conformation Capture and Sequencing; Chromosomal Rearrangement; Clonal Expansion; Complex; DNA; DNA Sequence Rearrangement; Data; Disease; Enhancers; Epigenetic Process; Gene Activation; Gene Dosage; Gene Expression; Gene Structure; Genes; Genetic Transcription; Genome; Genomic Instability; Genomics; Humoral Immunities; Immune response; Immunoglobulin Somatic Hypermutation; Link; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant lymphoid neoplasm; Maps; Modeling; Molecular Conformation; Mutation; Nature; Oncogenes; Oncogenic; Organism; Patients; Pattern; Phenotype; Physiological; Probability; Process; Proliferating; Reaction; Regulator Genes; Regulatory Element; Research; Rest; Role; Site; Somatic Mutation; Structure; Structure of germinal center of lymph node; Transcriptional Activation; Tumor Suppressor Proteins; Variant; Work; cancer cell; cancer genomics; cell type; chromosome conformation capture; computer framework; gene interaction; gene network; genome sequencing; genomic locus; high risk; insight; large cell Diffuse non-Hodgkin' s lymphoma; malignant phenotype; meter; novel; patient derived xenograft model; programs; promoter; spatiotemporal; transcription factor; transcriptional reprogramming; transcriptome sequencing; tumor; tumorigenesis; whole genome

PROJECT SUMMARY/ABSTRACT Diffuse large B-cell lymphomas (DLBCL) arise from B-cells transiting different stages of the germinal center (GC) reaction. It has become clear that these tumors can co-opt regulatory circuits of normal B-cells to drive their own malignant phenotype. Prior studies observe an inverse correlation between the timing of transcriptional activation during reprogramming and the degree of topological reorganization near the gene locus. This suggests that the reorganization of the 3D genome is critical for B-cell development and highlights its importance in DLBCL. Regulatory hubs are highly interactive regions of enhancers that can form interactions with multiple genes within topologically associating domains (TADs) to induce gene activation at a higher probability than pairs of non-interacting genes within the same TAD. Hubs are often rewired during cell fate transitions. Recent work also suggests a new level of organization into broadly interactive networks called chromunities, which putatively allow for transboundary sharing of information and more extensive gene regulatory information critical for cell identity. Critical to understanding the mechanisms driving changes in gene networks is the study of how large-scale chromosomal rearrangements (structural variants, SVs) can co- opt regulatory elements to form aberrant or de novo chromunities, consequently driving aberrant gene expression. While the interpretation of complex structural variants (SVs) has focused primarily on gene dosage and disruption by aberrant TAD structures, little is known regarding the role of SVs in reprogramming regulatory hubs and their target genes. To investigate the role of chromunities and its associated hubs in cell fate transitions and oncogenesis, we will leverage chromatin conformation capture interaction maps (pcHiC, Pore-C) to develop a computational framework to nominate chromunities and map networks of enhancer and promoters driving epigenetic and transcriptional reprogramming. We will also integrate chromatin contact maps with WGS data to investigate the role of complex SVs in reprogramming chromunities in lymphomas. Here, we hypothesize that physiological reprogramming of chromunity regulatory elements creates de novo coordination between sets of genes required to establish specific cell states and phenotypes during the humoral immune response and that SVs occurring in DLBCL alter these hub structures or create new ones leading to selective advantage of malignant clones. In our first aim, we will integrate transcriptional, epigenetic, and chromatin conformation capture assays to identify chromunities and their regulatory elements associated with establishing cell identity in the GC reaction. In our second aim, we will characterize the genomic rearrangement landscapes of B-cell lymphomas and how these directly link to hubs and chromunities using patient-derived xenograft models by generating matched WGS, Pore-C, and RNA-seq data.

项目摘要/摘要 扩散的大B细胞淋巴瘤（DLBCL）是由B细胞转变为生发中心不同阶段的B细胞 （GC）反应。很明显，这些肿瘤可以选择正常B细胞​​的调节电路以驱动 他们自己的恶性表型。先前的研究观察到时间之间的相关性 重编程过程中的转录激活和基因附近的拓扑重组程度 轨迹。这表明3D基因组的重组对于B细胞开发至关重要，并突出显示 它在DLBCL中的重要性。监管中心是可以形成的增强剂的高度交互区域 与拓扑关联的域（TAD）中与多个基因的相互作用，以诱导在A处的基因激活 比同一TAD内的非相互作用基因对比对更高。轮毂经常在单元格期间重新连接 命运过渡。最近的工作还提出了一个新的组织，该组织为广泛的交互式网络称为 色度，据推测允许跨界信息共享和更广泛的基因 调节信息对细胞身份至关重要。了解推动变化的机制至关重要 基因网络是对大规模染色体重排（结构变体，SV）的研究 选择调节元素形成异常或从头形状的形成，因此驱动异常基因 表达。虽然复杂结构变体（SV）的解释主要集中在基因上 剂量和因异常TAD结构的破坏，关于SV在重编程中的作用知之甚少 监管中心及其靶基因。调查色彩及其相关枢纽在细胞中的作用 命运过渡和肿瘤发生，我们将利用染色质构象捕获相互作用图（PCHIC，PCHIC， 孔C）开发一个计算框架，以提名增强剂和地图网络 驱动表观遗传和转录重编程的启动子。我们还将整合染色质接触图 使用WGS数据研究复杂SV在重编程淋巴瘤中的作用。在这里，我们 假设Chromunity调节元素的生理重编程会产生从头协调 在体液免疫期间建立特定细胞态和表型所需的基因组之间 响应，并且在DLBCL中发生的SV会改变这些集线器结构或创建新的结构，从而导致选择性 恶性克隆的优势。在我们的第一个目标中，我们将整合转录，表观遗传和染色质 构象捕获测定法，以识别与 在GC反应中建立细胞身份。在我们的第二个目标中，我们将表征基因组 B细胞淋巴瘤的重排景观以及它们如何直接与集线器和色彩链接 通过生成匹配的WGS，孔隙C和RNA-Seq数据，患者来源的异种移植模型。