title: A dose-dependent role for EBF1 in repressing non-B-cell-specific genes.
abstract: In the absence of early B-cell factor 1 (EBF1), B-cell development is arrested at an uncommitted progenitor stage that exhibits increased lineage potentials. Previously, we investigated the roles of EBF1 and its DNA-binding partner Runx1 by evaluating B lymphopoiesis in single (EBF1(het) and Runx1(het)) and compound haploinsufficent (Ebf1(+/-) Runx1(+/-), ER(het)) mice. Here, we demonstrate that decreased Ebf1 gene dosage results in the inappropriate expression of NK-cell lineage-specific genes in B-cell progenitors. Moreover, prolonged expression of Ly6a/Sca-1 suggested the maintenance of a relatively undifferentiated phenotype. These effects were exacerbated by reduced expression of Runx1 and occurred despite expression of Pax5. Repression of inappropriately expressed genes was restored in most pre-B and all immature B cells of ER(het) mice. Enforced EBF1 expression repressed promiscuous transcription in pro-B cells of ER(het) mice and in Ebf1(-/-) Pax5(-/-) fetal liver cells. Together, our studies suggest that normal levels of EBF1 are critical for maintaining B-cell identity by directing repression of non-B-cell-specific genes.
authors.affiliation: Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Lukin
authors.forename: Scott
authors.initials: S
authors.lastname: Fields
authors.forename: Lisa
authors.initials: L
authors.lastname: Guerrettaz
authors.forename: Desiree
authors.initials: D
authors.lastname: Straign
authors.forename: Valerie
authors.initials: V
authors.lastname: Rodriguez
authors.forename: Sasan
authors.initials: S
authors.lastname: Zandi
authors.forename: Robert
authors.initials: R
authors.lastname: Månsson
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.forename: James
authors.initials: J
authors.lastname: Hagman
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018628:Gene Dosage / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D051757:PAX5 Transcription Factor / Q000235:genetics; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000943:Antigens, Differentiation; D000950:Antigens, Ly; C489921:Ebf1 protein, mouse; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D015534:Trans-Activators