title: The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor.
abstract: Recent studies have identified a number of transcriptional regulators, including E proteins, EBF1, FOXO1, and PAX5, that act together to orchestrate the B-cell fate. However, it still remains unclear as to how they are linked at the earliest stages of B-cell development. Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A(+/-)HEB(-/-) mice is completely blocked at the LY6D(-) common lymphoid progenitor stage. We show that the transcription signatures of E2A- and HEB-ablated common lymphoid progenitors significantly overlap. Notably, we found that Foxo1 expression was substantially reduced in the LY6D(-) HEB- and E2A-deficient cells. Finally, we show that E2A binds to enhancer elements across the FOXO1 locus to activate Foxo1 expression, linking E2A and FOXO1 directly in a common pathway. In summary, the data indicate that the earliest event in B-cell specification involves the induction of FOXO1 expression and requires the combined activities of E2A and HEB.
authors.affiliation: Department of Molecular Biology, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Welinder
authors.forename: Robert
authors.initials: R
authors.lastname: Mansson
authors.forename: Elinore M
authors.initials: EM
authors.lastname: Mercer
authors.forename: David
authors.initials: D
authors.lastname: Bryder
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.forename: Cornelis
authors.initials: C
authors.lastname: Murre
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000276:immunology; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000276:immunology; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000276:immunology; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000950:Antigens, Ly; D051792:Basic Helix-Loop-Helix Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D058851:GPI-Linked Proteins; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; C467200:Foxo1 protein, mouse; C497452:Idb2 protein, mouse; C035271:Ly6d protein, mouse; C489532:Tcf12 protein, mouse; C075668:Tcf3 protein, mouse; C067679:Idb3 protein, mouse