Function and Regulation of Early B Cell Factor (EBF)

描述（由申请方提供）：早期B细胞因子（EBF）是B淋巴细胞中基因的重要调节因子。EBF通过激活编码前B和成熟B细胞受体（前BCR和BCR）的基因，驱动B细胞从早期祖细胞发育为成熟B细胞。在缺乏EBF的小鼠中，B细胞发育被阻止，免疫球蛋白不产生，EBF靶基因不被激活。在缺乏EBF mb-1（Ig-a）基因保持在高甲基化，不可接近的染色质。最近，我们证明，EBF是必需的，而且确实，启动CpG去甲基化和重塑核小体在B细胞特异性MB-1启动子。EBF对染色质的重塑促进了B谱系定型因子Pax 5与启动子的结合。我们的研究确定了一个新的转录因子的“功能”层次结构，除了以前确定的“遗传”层次结构（EBF调节pax 5的表达）。我们已经提出，EBF决定B谱系主要是其作为染色质重塑“先锋因子”的重要作用的函数。为了理解EBF如何驱动B谱系决定，我们建议1）鉴定EBF在B谱系特化中重要的基因靶点，2）确定EBF如何启动mb-1启动子的去甲基化，3）确定EBF依赖性染色质重塑的分子基础。

DESCRIPTION (provided by applicant): Early B cell Factor (EBF) is an essential regulator of genes in B lymphocytes. EBF drives B cell development from early progenitors to mature B cells by activating genes encoding the pre-B and mature B cell receptors (pre-BCR and BCR). In mice lacking EBF, B cell development is arrested, immunoglobulins are not produced and EBF target genes are not activated. In the absence of EBF mb-1 (Ig-a) genes remain in hypermethylated, inaccessible chromatin. Recently, we demonstrated that EBF is required for, and indeed, initiates CpG demethylation and remodeling of nucleosomes at the B cell-specific mb-1 promoter. Remodeling of chromatin by EBF facilitates binding of the promoter by the B lineage commitment factor Pax5. Our studies identified a new 'functional' hierarchy of transcription factors that acts in addition to the 'genetic' hierarchy identified previously (EBF regulates expression of pax5). We have proposed that B lineage determination by EBF is largely a function of its essential role as a chromatin remodeling 'pioneer factor'. To understand how EBF drives B lineage determination, we propose to 1) identify gene targets of EBF that are important in B lineage specification, 2) determine how EBF initiates demethylation of the mb-1 promoter and 3) determine the molecular basis of EBF-dependent chromatin remodeling.