表观调控蛋白Cfp1在B细胞早期发育过程中的作用及机制研究

B细胞是人体内介导体液免疫反应的关键免疫细胞，而其发育与活化异常往往导致免疫缺陷、自身免疫病和B细胞淋巴瘤等。表观调控对于维持正常B细胞分化发育、B细胞响应抗原刺激等过程具有重要作用，但是表观调控在早期B细胞中的作用机制尚未完全阐明。申请人前期研究显示，表观调控因子Cfp1在B细胞中特异性敲除导致小鼠B细胞发育阻滞于pro-B阶段，且Cfp1缺失pro-B细胞重链基因V片段与DJ片段重排受损，B细胞分化发育相关基因表达下调，提示Cfp1可能通过影响B细胞发育关键基因的表观修饰来调控B细胞发育过程。基于上述结果，本项目拟开展如下研究：（1）分析Cfp1缺陷pro-B细胞的表型，明确Cfp1在B细胞发育中的调控作用；（2）通过高通量测序，明确Cfp1在B细胞发育阶段调控的靶基因及其作用机制。本研究成果有助于了解Cfp1在B细胞发育中的调控机制，有望为治疗B细胞发育异常相关疾病提供新干预靶点。

B lymphocytes are a key player in humoral immunity and abnormality in B cell development and activation generally causes clinical diseases including immune deficiency, autoimmune diseases and malignancy. Epigenetic regulation plays a vital role in B cell development, involving in differentiation of hematopoietic cells to B lineage and B cell activation in response of foreign antigens. However the mechanisms of the epigenetic regulation in B precursors have not fully been revealed. Here we show that conditional deletion of Cfp1 in B cells resulted in severe block of B cell development in pro-B stage. And Cfp1 deficiency caused defects to recombination of VH segments to DHJH segments in pro-B cells. RNA-seq data showed that genes involved in B cell differentiation were downregulated in Cfp1-deficient pro-B cells. These data indicated that Cfp1 might play an important role in B cell development by regulating H3K4me3 deposition in target genes. Given these results, we plan to carry on the following experiments: (1) analyzing the phenotype of Cfp1-deficient pro-B cells to reveal the function of Cfp1 in B cell development; (2) screening Cfp1-targeted genes in B cells and figuring out the underlying mechanisms. This study will help to understand the epigenetic-regulating role of Cfp1 in B cell development and is hopeful to provide new therapeutic targets for B cell-related diseases.