Linking genome variation to transcriptional network dynamics in human B cells

免疫系统的B细胞是分析基因调控网络的主要模型 （GRNs）和细胞类型特异性转录控制机制。他们代表了一个特色 哺乳动物细胞在ENCODE项目中的状态，深入染色质和转录因子 侧写此外，编码抗体重链和轻链基因（IgH和IgL）的基因座 已被用于揭示体细胞DNA重组和超突变的新机制 这使得能够产生高度多样化的抗体库和亲和力成熟， 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 尽管取得了这些令人印象深刻的进展，但还没有一个全面的尝试， 描绘了人原代B细胞在其静息、活化和 终末分化状态或组装信号传导诱导的基因调控 控制B细胞的活化动力学和分化的网络。这 阻碍了系统地分析基因组变异对人类健康的影响的努力。 人类B细胞调控网络的结构和时间动态 健康和疾病。基于我们成功组装了第一个完整的顺式调节基因组 为原代小鼠B细胞通过耦合结构和功能基因组学，一个跨学科 研究小组提出要解决上述人类B细胞的两个主要挑战。因此，在本发明中， 我们希望提出一个可推广的框架，用于分析 人类基因组变异和动态基因网络调控。

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.