2012年11月21日 訊 /生物谷BIOON/ --血細(xì)胞發(fā)育過程稱為造血，使人產(chǎn)生許多不同的免疫細(xì)胞亞型?，F(xiàn)有研究認(rèn)為三種轉(zhuǎn)錄因子E2A,，EBF1和PAX5促使功能性B淋巴細(xì)胞成熟,。近日,，Wooseok等研究人員證實(shí)E2A是EBF1表達(dá)的所必需的。Seo和Taniuchi研究了另一種轉(zhuǎn)錄因子Runx1,，Runx1是血細(xì)胞發(fā)育的一個(gè)重要組成部分,。沒有Runx1，造血是不可能發(fā)生的,。
研究人員利用除了早期B細(xì)胞前體,，每一個(gè)細(xì)胞都表達(dá)Runx1的轉(zhuǎn)基因工程小鼠來探究Runx1在B細(xì)胞發(fā)育中的作用。結(jié)果發(fā)現(xiàn)沒有Runx1,，這些細(xì)胞停滯在發(fā)育的早期,。
Seo和他的同事們證實(shí)Runx1聯(lián)合Cbfβ蛋白，通常結(jié)合調(diào)節(jié)EBF1生成的啟動(dòng)子序列上,。有趣的是,，EBF1有兩種截然不同的啟動(dòng)子，RUNX1-Cbfβ和E2A每個(gè)綁定到EBF1不同的啟動(dòng)子上,。
在Runx1存在情況下,，EBF1基因活性大幅降低，能阻斷EBF1下游誘導(dǎo)的B細(xì)胞分化的最后一步,。然而，Runx1能開啟編碼其上游激活因子E2A的基因,，激活正反饋環(huán)路,，從而加速B細(xì)胞分化過程，因此,，如果沒有Runx1,，三個(gè)分化因素就不會(huì)正確表達(dá)。
目前,，研究人員正在探索Runx1控制基因活性的機(jī)制,，以及是如何能夠發(fā)揮這樣一個(gè)強(qiáng)有力的促造血發(fā)育功能的。（生物谷：Bioon.com）
doi:10.1084/jem.20112745
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PMID:
Runx1–Cbfβ facilitates early B lymphocyte development by regulating expression of Ebf1.
Seo, W., Ikawa, T., Kawamoto, H. & Taniuchi, I.
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.
