Linking genome variation to transcriptional network dynamics in human B cells

将基因组变异与人类 B 细胞转录网络动态联系起来

• 批准号: 10297231
• 负责人: Jishnu Das
• 金额: $ 95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-19 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297231
• 关键词: ATAC-seq; Address; Antibodies; Antibody Affinity; Antibody Repertoire; Autoimmune Diseases; B cell differentiation; B-Lymphocytes; Biological; Catalogs; Cell Line; Cells; Cellular biology; ChIP-seq; Chromatin; Computer Analysis; Coupled; Coupling; Data; Data Set; Disease; Elements; Enhancers; FAIRE sequencing; Gene Expression Profile; Gene Expression Profiling; Generations; Genes; Genetic Recombination; Genetic Transcription; Genome; Genomic approach; Genomics; Health; Hi-C; Human; Human Genome; Human Herpesvirus 4; Immune System Diseases; Immune system; Immunologist; Insulin-Dependent Diabetes Mellitus; Libraries; Light; Link; Linkage Disequilibrium; Machine Learning; Mammalian Cell; Maps; Modeling; Mus; Network-based; Output; Patients; Plasma Cells; Regulation; Regulator Genes; Resolution; Rest; Signal Transduction; Structure; System; Systemic Lupus Erythematosus; Testing; Training; Transcriptional Regulation; Untranslated RNA; Vaccines; Variant; base; biobank; cell type; experimental analysis; functional genomics; genetic regulatory protein; genetic variant; genome editing; genome wide association study; genomic profiles; genomic variation; next generation; novel; pathogen; promoter; response; screening; structural genomics; success; transcription factor; transcriptome sequencing; vaccine response

B cells of the immune system are a leading model for the analysis of gene regulatory networks (GRNs) and cell type specific transcriptional control mechanisms. They represent a featured mammalian cell state in the ENCODE project for in depth chromatin and transcription factor profiling. Furthermore, the loci encoding the antibody heavy and light chain genes (IgH and IgL) have been used to uncover novel mechanisms of somatic DNA recombination and hypermutation that enable the generation of highly diverse antibody repertoires and affinity maturation in response to pathogen encounters or vaccines. Importantly, variation in the human B cell regulatory genome has been associated with autoimmune diseases and vaccine responses. In spite of these impressive advances, there has not been a comprehensive attempt to delineate the cis-regulome of primary human B cells in their resting, activated and terminally differentiated states or to assemble a signaling induced gene regulatory network that controls the activation dynamics and differentiation of B cells. This has impeded efforts to systematically analyze the consequences of genomic variation on the structure and temporal dynamics of the underlying B cell regulatory network in human health and disease. Based on our success in assembling the first comprehensive cis-regulome for primary murine B cells by coupling structural and functional genomics, an inter-disciplinary team is proposing to address the two major challenges highlighted above for human B cells. Thus, we hope to advance a generalizable framework for analyzing the causal connections between human genome variation and dynamic gene network regulation in diverse biological contexts.

免疫系统的B细胞是分析基因调控网络的主要模型。 (GRN)和细胞类型特定的转录调控机制。他们代表了一种特色 哺乳动物细胞在深度染色质和转录因子编码计划中的状态 侧写。此外，编码抗体重链和轻链基因(IgH和IGL)的基因座 已被用来揭示体细胞DNA重组和超突变的新机制 能够产生高度多样化的抗体谱系和亲和力成熟 对病原体或疫苗的反应。重要的是，人类B细胞的变异 调节基因组与自身免疫性疾病和疫苗反应有关。在……里面 尽管取得了这些令人印象深刻的进展，但还没有全面的尝试 人原代B细胞在静息、激活和激活状态下的顺式调控组 终末分化状态或组装信号诱导的基因调控 控制B细胞的激活动态和分化的网络。这有 阻碍了系统分析基因组变异对人类健康的影响 人类基本B细胞调控网络的结构和时间动力学 健康和疾病。基于我们成功组装了第一个全面的顺式调控组 通过耦合结构和功能基因组学对原代小鼠B细胞，一个跨学科的 该团队建议解决上述人类B细胞面临的两大挑战。因此， 我们希望提出一个分析两者之间因果关系的通用框架。 不同生物背景下的人类基因组变异和动态基因网络调控。