Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 209, Issue 7, Pages 1255-1262Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20112745
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Funding
- Uehara Memorial Foundation
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Postdoctoral Fellowship for Foreign Researchers from the Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [10F00516, 22118004] Funding Source: KAKEN
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Although Runx and Cbf beta transcription factor complexes are involved in the development of multiple hematopoietic lineages, their precise roles in early mouse B lymphocyte differentiation remain elusive. In this study, we examined mouse strains in which Runx1, Runx3, or Cbf beta were deleted in early B lineage progenitors by an mb1-cre transgene. Loss of Runx1, but not Runx3, caused a developmental block during early B lymphopoiesis, resulting in the lack of IgM(+) B cells and reduced V-H to DJ(H) recombination. Expression of core transcription factors regulating early B cell development, such as E2A, Ebf1, and Pax5, was reduced in B cell precursors lacking Runx1. We detected binding of Runx1-Cbf beta complexes to the Ebf1 proximal promoter, and these Runx-binding motifs were essential to drive reporter gene expression. Runx1-deficient pro-B cells harbored excessive amounts of the repressive histone mark H3K27 trimethylation in the Ebf1 proximal promoter. Interestingly, retroviral transduction of Ebf1, but not Pax5, into Runx1-deficient progenitors restored not only development of B220(+) cells that underwent V-H to DJ(H) rearrangement but also expression of B lineage signature genes. Collectively, these results demonstrate that Runx1-Cbf beta complexes are essential to facilitate B lineage specification, in part via epigenetic activation of the Ebf1 gene.
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