Journal
BLOOD
Volume 121, Issue 10, Pages 1769-1782Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-08-450114
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Funding
- Medical Research Council, UK
- Lymphoma and Leukaemia Research
- Spanish Ministry of Education
- Chinese Excellence Award
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0405] Funding Source: researchfish
- Medical Research Council [MC_U120027516, MC_U120097112] Funding Source: researchfish
- BBSRC [BBS/E/B/000C0405] Funding Source: UKRI
- MRC [MC_U120027516, MC_U120097112] Funding Source: UKRI
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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.
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