Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation
Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation
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DOI：
10.1182/blood-2012-08-450114
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发表时间：
2013-03-07
期刊：
影响因子：
20.3
通讯作者：
Merkenschlager, Matthias
中科院分区：
文献类型：
--
作者：
Ferreiros-Vidal, Isabel;Carroll, Thomas;Merkenschlager, Matthias
Ikaros家族DNA结合蛋白是B细胞发育的关键调节因子。由于目前对B细胞祖细胞中Ikaros靶点的了解有限，我们已经鉴定了前B细胞中受Ikaros结合和调控的基因。为了阐明Ikaros在B细胞谱系特化和分化中的作用，我们分析了多能祖细胞向淋巴限制性祖细胞发展、B细胞和T细胞谱系特化以及沿着B细胞谱系发展过程中Ikaros靶点的差异表达。Ikaros靶点占体内B细胞谱系特化过程中上调的所有基因的一半，解释了Ikaros在此过程中的重要作用。Ikaros旁系同源物Ikzf1和Ikzf3的表达在B细胞祖细胞分化过程中逐渐增加，并且值得注意的是，在循环前B细胞中的可诱导Ikaros表达足以驱动类似于体内循环至静息前B细胞的分化的转录变化。这些数据表明，Ikaros转录因子剂量通过调节关键途径中的多个靶点，包括前B细胞受体信号传导、细胞周期进程和淋巴细胞受体重排，驱动祖细胞沿着预定谱系进展。我们的方法可能是普遍使用的映射的转录因子对细胞谱系的承诺和分化的贡献。
Ikaros family DNA-binding proteins are critical regulators of B-cell development. Because the current knowledge of Ikaros targets in B-cell progenitors is limited, we have identified genes that are bound and regulated by Ikaros in pre-B cells. To elucidate the role of Ikaros in B-cell lineage specification and differentiation, we analyzed the differential expression of Ikaros targets during the progression of multipotent to lymphoid-restricted progenitors, B-and T-cell lineage specification, and progression along the B-cell lineage. Ikaros targets accounted for one-half of all genes up-regulated during B-cell lineage specification in vivo, explaining the essential role of Ikaros in this process. Expression of the Ikaros paralogs Ikzf1 and Ikzf3 increases incrementally during B-cell progenitor differentiation, and, remarkably, inducible Ikaros expression in cycling pre-B cells was sufficient to drive transcriptional changes resembling the differentiation of cycling to resting pre-Bcells in vivo. The data suggest that Ikaros transcription factor dosage drives the progression of progenitors along a predetermined lineage by regulating multiple targets in key pathways, including pre-B-cell receptor signaling, cell cycle progression, and lymphocyte receptor rearrangement. Our approachmay be of general use to map the contribution of transcription factors to cell lineage commitment and differentiation.