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Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate
- Mansson, Robert, Welinder, Eva, Åhsberg, Josefine, Lin, Yin C., Benner, Christopher, Glass, Christopher K., Lucas, Joseph S., Sigvardsson, Mikael, Murre, Cornelis
- Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.51 pp. 21028-21033
- B-lymphocytes, genes, messenger RNA, mice, phenotype, transcription factors
- 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.