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

项目总结/摘要 弥漫性大B细胞淋巴瘤（DLBCL）是由B细胞通过生殖中心的不同阶段引起的 (GC)反应很明显，这些肿瘤可以选择正常B细胞的调节回路， 自身的恶性表型先前的研究观察到， 重编程过程中的转录激活和基因附近的拓扑重组程度 基因座这表明3D基因组的重组对B细胞发育至关重要，并强调了 在DLBCL中的重要性。调节中心是增强子的高度相互作用区域， 与拓扑相关结构域（TADs）内的多个基因相互作用，以诱导基因激活， 比同一个基因组中的非相互作用基因对的概率更高。集线器通常在单元期间重新布线 命运的变迁最近的研究还表明，广泛互动的网络组织达到了一个新的水平， 染色质，这使得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。关键是要了解驱动变化的机制， 基因网络是研究大规模的染色体重排（结构变异，SV）如何共同作用， 选择调节元件以形成异常或新生的染色质，从而驱动异常基因 表情虽然对复杂结构变异（SV）的解释主要集中在基因突变上， 剂量和破坏异常的神经元结构，很少有人知道的作用，SV在重编程 调控中心及其靶基因。研究细胞色素及其相关枢纽在细胞内的作用， 命运转换和肿瘤发生，我们将利用染色质构象捕获相互作用图谱（pcHiC， Pore-C）开发一个计算框架来命名增强子和增强子的色度和映射网络， 启动子驱动表观遗传和转录重编程。我们还将整合染色质接触图 用WGS数据研究复杂SV在淋巴瘤重编程中的作用。这里我们 假设染色调节元件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 在DLBCL中发生的SV改变了这些枢纽结构或产生新的枢纽结构，导致选择性免疫应答。 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，以鉴定与 在GC反应中建立细胞身份。在我们的第二个目标中，我们将描述基因组 B细胞淋巴瘤的重排景观，以及这些如何直接连接到枢纽和染色质使用 通过生成匹配的WGS、Pore-C和RNA-seq数据，对患者来源的异种移植物模型进行研究。

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.