Runx1-Cbfβ facilitates early B lymphocyte development by regulating expression of Ebf1.
Although Runx and Cbfβ 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 Cbfβ 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-Cbfβ 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-Cbfβ complexes are essential to facilitate B lineage specification, in part via epigenetic activation of the Ebf1 gene.
Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama 230-0045, Japan.
Wooseok
W
Seo
Tomokatsu
T
Ikawa
Hiroshi
H
Kawamoto
Ichiro
I
Taniuchi
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D050658:Core Binding Factor beta Subunit / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D060152:V(D)J Recombination / Q000235:genetics
D050676:Core Binding Factor Alpha 2 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D050658:Core Binding Factor beta Subunit; C489921:Ebf1 protein, mouse; D015534:Trans-Activators