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

Mansson, Robert; Welinder, Eva LU ; Ahsberg, Josefine; Lin, Yin C.; Benner, Christopher; Glass, Christopher K.; Lucas, Joseph S.; Sigvardsson, Mikael and Murre, Cornelis (2012) In Proceedings of the National Academy of Sciences 109(51). p.21028-21033
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.... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
109
issue
51
pages
21028 - 21033
publisher
National Acad Sciences
external identifiers
  • wos:000313123700059
  • scopus:84871390259
ISSN
1091-6490
DOI
10.1073/pnas.1211427109
language
English
LU publication?
yes
id
8826ec9a-b483-4fc5-99eb-29cbed0bd1bb (old id 3481617)
date added to LUP
2013-03-01 07:50:41
date last changed
2017-10-22 03:24:02
@article{8826ec9a-b483-4fc5-99eb-29cbed0bd1bb,
  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.},
  author       = {Mansson, Robert and Welinder, Eva and Ahsberg, Josefine and Lin, Yin C. and Benner, Christopher and Glass, Christopher K. and Lucas, Joseph S. and Sigvardsson, Mikael and Murre, Cornelis},
  issn         = {1091-6490},
  language     = {eng},
  number       = {51},
  pages        = {21028--21033},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate},
  url          = {http://dx.doi.org/10.1073/pnas.1211427109},
  volume       = {109},
  year         = {2012},
}