Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-12, Vol.109 (51), p.21028-21033
• Main Authors: Mansson, Robert, Welinder, Eva, Åhsberg, Josefine, Lin, Yin C., Benner, Christopher, Glass, Christopher K., Lucas, Joseph S., Sigvardsson, Mikael, Murre, Cornelis
• Format: Article
• Language: English
• Subjects: Animals; B lymphocytes; B-Lymphocytes - cytology; B-Lymphocytes - immunology; Basic Medicine; Biological Sciences; Cell Lineage; Cell lines; Cell Separation; Cells; Enhancer Elements, Genetic; Feedback circuits; Feedback, Physiological; Flow Cytometry; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Gene Expression Regulation; Genes; Genomes; Genotype & phenotype; Immunologi inom det medicinska området; Immunology in the medical area; Luciferases - metabolism; Medical and Health Sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Medicinska och farmaceutiska grundvetenskaper; messenger RNA; Mice; Models, Biological; Models, Genetic; phenotype; Positive feedback; Progenitor cells; Ribonucleic acid; RNA; Signatures; Stem cells; Trans-Activators - physiology; Transcription factors; Transcription, Genetic
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1211427109

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.