Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation

被引：95

作者：

Ferreiros-Vidal, Isabel ^{[1
,2
]}

Carroll, Thomas ^{[2
]}

Taylor, Benjamin ^{[1
,2
]}

Terry, Anna ^{[1
,2
]}

Liang, Ziwei ^{[1
,2
]}

Bruno, Ludovica ^{[1
,2
]}

Dharmalingam, Gopuraja ^{[2
]}

Khadayate, Sanjay ^{[2
]}

Cobb, Bradley S. ^{[1
,2
]}

Smale, Stephen T. ^{[3
]}

Spivakov, Mikhail ^{[4
]}

Srivastava, Prashant ^{[5
]}

Petretto, Enrico ^{[5
]}

Fisher, Amanda G. ^{[1
,2
]}

Merkenschlager, Matthias ^{[1
,2
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC, Lymphocyte Dev Grp,Clin Sci Ctr, London W12 0NN, England

[2] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC, Epigenet Sect,Clin Sci Ctr, London W12 0NN, England

[3] Univ Calif Los Angeles, Inst Mol Biol, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA

[4] European Bioinformat Inst, Cambridge, England

[5] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC, Integrat Genom & Med Grp,Clin Sci Ctr, London W12 0NN, England

来源：

BLOOD | 2013年 / 121卷 / 10期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

TRANSCRIPTION FACTORS; LYMPHOBLASTIC-LEUKEMIA; RECEPTOR; NETWORK; EXPRESSION; AIOLOS; CYCLE; PROLIFERATION; REPRESSION; PROTEINS;

D O I：

10.1182/blood-2012-08-450114

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：1769 / 1782

页数：14

共 45 条

[1]

FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination [J].