title: Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation.
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.
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferreirós-Vidal
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.forename: Benjamin
authors.initials: B
authors.lastname: Taylor
authors.forename: Anna
authors.initials: A
authors.lastname: Terry
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Liang
authors.forename: Ludovica
authors.initials: L
authors.lastname: Bruno
authors.forename: Gopuraja
authors.initials: G
authors.lastname: Dharmalingam
authors.forename: Sanjay
authors.initials: S
authors.lastname: Khadayate
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Cobb
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smale
authors.forename: Mikhail
authors.initials: M
authors.lastname: Spivakov
authors.forename: Prashant
authors.initials: P
authors.lastname: Srivastava
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D001665:Binding Sites; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D016678:Genome; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D051740:Ikaros Transcription Factor