Early B cell Factor (EBF) is essential for the development of B lymphocytes from early progenitor cells. EBF regulates the mb-1 gene, which encodes Ig-alpha a protein required for display of immunoglobulin (Ig) on the plasma membrane and transmembrane signaling following stimulation of the B cell receptor (BCR). Cell surface expression of the BCR and the surrogate pro-BCR and pre-BCR at early stages of development is very precisely regulated, and this regulation is critical for proper development and function of B cells. We have observed changes in levels of mb-1 transcripts in cell lines representing different stages of development and in ex vivo B cells following stimulation by polyvalent antigen. As a potential mechanism for setting the level of Ig-alpha in B cells, we recently defined constellations of nuclear factors required for high vs. low level mb-1 transcription at different stages of B cell development. High level transcription requires EBF, the basic-helix-loop-helix (HLH) factor E2A, and the Runt domain protein Runxl (and its coactivator CBFbeta), which assemble higher order complexes on the mb-1 promoter. We propose that the intracellular concentration of Ig-alpha, and thus, expression of the BCR on the surface of B cells, is regulated by EBF and associated proteins. To better understand the molecular biology of EBF, we will determine how it controls B cell development and BCR density, and thus, the response of B cells to antigen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI054661-01A1
Application #
6732239
Study Section
Immunobiology Study Section (IMB)
Program Officer
Nasseri, M Faraz
Project Start
2004-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$299,330
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Dege, Carissa; Hagman, James (2013) Activation of Aicda gene transcription by Pax5 in plasmacytoma cells. Immunol Res 55:155-61
Collins, Bernard; Clambey, Eric T; Scott-Browne, James et al. (2013) Ikaros promotes rearrangement of TCR ? genes in an Ikaros null thymoma cell line. Eur J Immunol 43:521-32
Hagman, James; Ramírez, Julita; Lukin, Kara (2012) B lymphocyte lineage specification, commitment and epigenetic control of transcription by early B cell factor 1. Curr Top Microbiol Immunol 356:17-38
Lettice, Laura A; Williamson, Iain; Wiltshire, John H et al. (2012) Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev Cell 22:459-67
Ramírez, Julita; Dege, Carissa; Kutateladze, Tatiana G et al. (2012) MBD2 and multiple domains of CHD4 are required for transcriptional repression by Mi-2/NuRD complexes. Mol Cell Biol 32:5078-88
Lukin, Kara; Fields, Scott; Guerrettaz, Lisa et al. (2011) A dose-dependent role for EBF1 in repressing non-B-cell-specific genes. Eur J Immunol 41:1787-93
Lin, Yin C; Jhunjhunwala, Suchit; Benner, Christopher et al. (2010) A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat Immunol 11:635-43
Ramírez, Julita; Lukin, Kara; Hagman, James (2010) From hematopoietic progenitors to B cells: mechanisms of lineage restriction and commitment. Curr Opin Immunol 22:177-84
Lukin, Kara; Fields, Scott; Lopez, Desiree et al. (2010) Compound haploinsufficiencies of Ebf1 and Runx1 genes impede B cell lineage progression. Proc Natl Acad Sci U S A 107:7869-74
Hong, Xia; Zang, Jianye; White, Janice et al. (2010) Interaction of JMJD6 with single-stranded RNA. Proc Natl Acad Sci U S A 107:14568-72

Showing the most recent 10 out of 22 publications