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.

项目概要/摘要 弥漫性大 B 细胞淋巴瘤 (DLBCL) 由穿越生发中心不同阶段的 B 细胞引起 （气相色谱）反应。很明显，这些肿瘤可以选择正常 B 细胞的调节回路来驱动 他们自己的恶性表型。先前的研究观察到，时间之间存在负相关性。 重编程过程中的转录激活以及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 细胞发育至关重要，并强调 它在 DLBCL 中的重要性。监管中心是增强子高度互动的区域，可以形成 与拓扑关联域 (TAD) 内的多个基因相互作用，以诱导基因激活 比同一 TAD 内的非相互作用基因对更高的概率。集线器经常在电池期间重新接线 命运转变。最近的工作还提出了广泛互动网络的新组织水平，称为 色度，据推测允许跨界共享信息和更广泛的基因 对细胞身份至关重要的监管信息。对于理解推动变化的机制至关重要 基因网络是研究大规模染色体重排（结构变异，SV）如何共同作用的学科。 选择调控元件形成异常或从头染色，从而驱动异常基因 表达。虽然复杂结构变异（SV）的解释主要集中在基因上 异常 TAD 结构的剂量和破坏，关于 SV 在重编程中的作用知之甚少 调控中心及其靶基因。研究细胞中色团及其相关中枢的作用 命运转变和肿瘤发生，我们将利用染色质构象捕获相互作用图（pcHiC， Pore-C）开发一个计算框架来指定色度并映射增强子和 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 利用全基因组测序（WGS）数据来研究复杂的 SV 在淋巴瘤重编程染色中的作用。在这里，我们 假设色度调节元件的生理重编程产生从头协调 在体液免疫过程中建立特定细胞状态和表型所需的基因组之间 DLBCL 中发生的 SV 会改变这些中枢结构或创建新的中枢结构，从而导致选择性 恶性克隆的优势。我们的第一个目标是整合转录、表观遗传和染色质 构象捕获测定法识别色度及其相关的调控元件 在 GC 反应中确定细胞身份。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中枢和色团联系起来 通过生成匹配的 WGS、Pore-C 和 RNA-seq 数据来获得患者来源的异种移植模型。