Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate
2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 51, 21028-21033 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
National Academy of Sciences , 2012. Vol. 109, no 51, 21028-21033 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-88462DOI: 10.1073/pnas.1211427109ISI: 000313123700059OAI: oai:DiVA.org:liu-88462DiVA: diva2:604060
Funding Agencies|National Institutes of Health||2013-02-072013-02-072013-02-20