Document Detail


Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate.
MedLine Citation:
PMID:  23213261     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Robert Mansson; Eva Welinder; Josefine Åhsberg; Yin C Lin; Christopher Benner; Christopher K Glass; Joseph S Lucas; Mikael Sigvardsson; Cornelis Murre
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-12-04
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-19     Completed Date:  2013-02-28     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21028-33     Citation Subset:  IM    
Affiliation:
Department of Molecular Biology, University of California at San Diego, La Jolla, CA 92093, USA.
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE41931
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
B-Lymphocytes / cytology,  immunology*
Cell Lineage
Cell Separation
Enhancer Elements, Genetic
Feedback, Physiological
Flow Cytometry
Forkhead Transcription Factors / metabolism*
Gene Expression Regulation
Luciferases / metabolism
Mice
Models, Biological
Models, Genetic
Trans-Activators / physiology*
Transcription, Genetic
Grant Support
ID/Acronym/Agency:
R01 CA054198/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Ebf1 protein, mouse; 0/Forkhead Transcription Factors; 0/Foxo1 protein, mouse; 0/Trans-Activators; EC 1.13.12.-/Luciferases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Ubiquitylation of p53 by the APC/C inhibitor Trim39.
Next Document:  Human seizures self-terminate across spatial scales via a critical transition.