1. Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation.
- Author
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Ferreirós-Vidal I, Carroll T, Taylor B, Terry A, Liang Z, Bruno L, Dharmalingam G, Khadayate S, Cobb BS, Smale ST, Spivakov M, Srivastava P, Petretto E, Fisher AG, and Merkenschlager M
- Subjects
- Animals, B-Lymphocytes metabolism, Binding Sites, Cell Cycle, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Regulation, Ikaros Transcription Factor genetics, Lymphocyte Activation, Mice, Precursor Cells, B-Lymphoid metabolism, Signal Transduction, Transcription Factors genetics, B-Lymphocytes cytology, Cell Differentiation, Cell Lineage, Genome, Ikaros Transcription Factor metabolism, Precursor Cells, B-Lymphoid cytology, Transcription Factors metabolism
- Abstract
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.
- Published
- 2013
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