Runx1-Cbfβ facilitates early B lymphocyte development by regulating expression of Ebf1.
Runx1-Cbfβ facilitates early B lymphocyte development by regulating expression of Ebf1.
复制标题
DOI：
10.1084/jem.20112745
复制
发表时间：
2012-07-02
期刊：
影响因子：
--
通讯作者：
Taniuchi I
中科院分区：
文献类型：
--
作者：
Seo W;Ikawa T;Kawamoto H;Taniuchi I
Mb 1-Cre介导的Runx 1缺失损害B谱系发育并导致Ebf 1近端启动子上抑制性组蛋白标记的积累; Ebf 1而非Pax 5的异位表达恢复B细胞分化。虽然Runx和Cbfβ转录因子复合物参与多种造血谱系的发育，但它们在小鼠早期B淋巴细胞分化中的确切作用仍然是难以捉摸的。在这项研究中，我们检测了通过mb 1-cre转基因在早期B谱系祖细胞中缺失Runx 1、Runx 3或Cbfβ的小鼠品系。Runx 1的缺失，而不是Runx 3的缺失，导致早期B淋巴细胞生成过程中的发育阻滞，导致IgM+ B细胞的缺乏和VH至DJH重组的减少。在缺乏Runx 1的B细胞前体中，调控早期B细胞发育的核心转录因子如E2 A、Ebf 1和Pax 5的表达减少。我们检测到Runx 1-Cbfβ复合物与Ebf 1近端启动子的结合，这些Runx结合基序对驱动报告基因表达至关重要。Runx 1缺陷型前B细胞在Ebf 1近端启动子中含有过量的抑制性组蛋白标记H3 K27三甲基化。有趣的是，逆转录病毒转导Ebf 1，而不是Pax 5，进入Runx 1缺陷的祖细胞不仅恢复了B220+细胞的发展，经历了VH到DJH重排，但也表达B谱系签名基因。总的来说，这些结果表明Runx 1-Cbfβ复合物是促进B谱系特化所必需的，部分通过Ebf 1基因的表观遗传激活。
Mb1-Cre–mediated deletion of Runx1 impairs B lineage development and causes accumulation of repressive histone marks on the Ebf1 proximal promoter; ectopic expression of Ebf1 but not Pax5 restores B cell differentiation. Although Runx and Cbfβ transcription factor complexes are involved in the development of multiple hematopoietic lineages, their precise roles in early mouse B lymphocyte differentiation remain elusive. In this study, we examined mouse strains in which Runx1, Runx3, or Cbfβ were deleted in early B lineage progenitors by an mb1-cre transgene. Loss of Runx1, but not Runx3, caused a developmental block during early B lymphopoiesis, resulting in the lack of IgM+ B cells and reduced VH to DJH recombination. Expression of core transcription factors regulating early B cell development, such as E2A, Ebf1, and Pax5, was reduced in B cell precursors lacking Runx1. We detected binding of Runx1–Cbfβ complexes to the Ebf1 proximal promoter, and these Runx-binding motifs were essential to drive reporter gene expression. Runx1-deficient pro-B cells harbored excessive amounts of the repressive histone mark H3K27 trimethylation in the Ebf1 proximal promoter. Interestingly, retroviral transduction of Ebf1, but not Pax5, into Runx1-deficient progenitors restored not only development of B220+ cells that underwent VH to DJH rearrangement but also expression of B lineage signature genes. Collectively, these results demonstrate that Runx1–Cbfβ complexes are essential to facilitate B lineage specification, in part via epigenetic activation of the Ebf1 gene.
登录
查看更多内容
影响因子：
56.9
作者：
SCOTT, EW;SIMON, MC;SINGH, H
通讯作者：
SINGH, H
影响因子：
64.5
作者：
Taniuchi, I;Osato, M;Littman, DR
通讯作者：
Littman, DR
影响因子：
14.8
作者：
Dahl, John Arne;Collas, Philippe
通讯作者：
Collas, Philippe
影响因子：
30.5
作者：
Reynaud, Damien;Demarco, Ignacio A.;Singh, Harinder
通讯作者：
Singh, Harinder
影响因子：
32.4
作者：
Ikawa, T;Kawamoto, H;Murre, C
通讯作者：
Murre, C