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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Robert Mansson
  • Eva Welinder
  • Josefine Ahsberg
  • Yin C. Lin
  • Christopher Benner
  • Christopher K. Glass
  • Joseph S. Lucas
  • Mikael Sigvardsson
  • Cornelis Murre
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
Original languageEnglish
Pages (from-to)21028-21033
JournalProceedings of the National Academy of Sciences
Volume109
Issue number51
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes