title: Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate.
abstract: Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D(+) cell stage. We demonstrate that this phenotype closely resembles the arrest in B-cell development observed in EBF1-deficient mice. Consistent with these observations, we find that the transcription signatures of FOXO1- and EBF1-deficient LY6D(+) progenitors are strikingly similar, indicating a common set of target genes. Furthermore, we found that depletion of EBF1 expression in LY6D(+) CLPs severely affects FOXO1 mRNA abundance, whereas depletion of FOXO1 activity in LY6D(+) CLPs ablates EBF1 transcript levels. We generated a global regulatory network from EBF1 and FOXO1 genome-wide transcription factor occupancy and transcription signatures derived from EBF1- and FOXO1-deficient CLPs. This analysis reveals that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage.
authors.affiliation: Department of Molecular Biology, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Mansson
authors.forename: Eva
authors.initials: E
authors.lastname: Welinder
authors.forename: Josefine
authors.initials: J
authors.lastname: Åhsberg
authors.forename: Yin C
authors.initials: YC
authors.lastname: Lin
authors.forename: Christopher
authors.initials: C
authors.lastname: Benner
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Lucas
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.forename: Cornelis
authors.initials: C
authors.lastname: Murre
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019070:Cell Lineage; D002469:Cell Separation; D004742:Enhancer Elements, Genetic; D025461:Feedback, Physiological; D005434:Flow Cytometry; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C489921:Ebf1 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D015534:Trans-Activators; D008156:Luciferases