The overall objective of the research proposed in this application is to understand the molecular mechanisms that drive immunologic processes. It has become clear that the events that control lymphoid differentiation are a result of changing patterns of gene expression. The studies proposed here are focused on a class of transcription factors, helix-loop-helix proteins, that are in part responsible for the alterations in gene expression during B cell development. One particular class of helix- loop-helix (HLH) proteins are the E-proteins, that include E12, E47, E2-2 and HEB. E12 and E47 are encoded by one gene, E2A, and arise through differential splicing. E2-2 and HEB are encoded by different genes. The applicant showed previously that E2A gene products are required for proper B cell development. Differentiation of B cells in E2A mutant mice is blocked at a stage prior to immunoglobulin (Ig) gene rearrangement. Some B cell specific transcripts including B29 and Ig germline transcript - are expressed. Others, including RAG-1, RAG-2, mb-1, l5, VpreB and CD19 are absent. In addition, two transcription factors, including Pax -5 and EBF, implicated in the regulation of CD19 and mb-1 respectively, are absent in E2A (-/-) mice. These data suggested that E2A is a central regulator in early B cell development. It is proposed to continue these studies.
The specific aims of the are focused on a further understanding of the role of E-proteins in B cell development. Specifically, the applicant plans to examine the individual roles of E12 and E47 in B cell differentiation. He will examine whether E12 or E47 regulate PAX-5 and EBF expression. The individual roles of Pax-5 and EBF in generating the E2A deficient phenotype will be studied. The role of E2-2 in lymphoid development will be investigated using gene targeting. It is planned to use transgenic mice to further dissect the contributions and redundancies of E-proteins in B cell development. Finally, the applicant will perform a genetic analysis of transcription factors in B cell development, including E-proteins, Oct-2 and PU.1.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
Zip Code
Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Shuwen et al. (2014) Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nat Immunol 15:767-76
Lin, Yin C; Benner, Christopher; Mansson, Robert et al. (2012) Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate. Nat Immunol 13:1196-204
Mansson, Robert; Welinder, Eva; Ã…hsberg, Josefine et al. (2012) Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate. Proc Natl Acad Sci U S A 109:21028-33
Lucas, Joseph S; Bossen, Claudia; Murre, Cornelis (2011) Transcription and recombination factories: common features? Curr Opin Cell Biol 23:318-24
Guo, Chunguang; Yoon, Hye Suk; Franklin, Andrew et al. (2011) CTCF-binding elements mediate control of V(D)J recombination. Nature 477:424-30
Mercer, Elinore M; Lin, Yin C; Benner, Christopher et al. (2011) Multilineage priming of enhancer repertoires precedes commitment to the B and myeloid cell lineages in hematopoietic progenitors. Immunity 35:413-25
Mercer, Elinore M; Lin, Yin C; Murre, Cornelis (2011) Factors and networks that underpin early hematopoiesis. Semin Immunol 23:317-25
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
Heinz, Sven; Benner, Christopher; Spann, Nathanael et al. (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38:576-89
Jhunjhunwala, Suchit; van Zelm, Menno C; Peak, Mandy M et al. (2009) Chromatin architecture and the generation of antigen receptor diversity. Cell 138:435-48

Showing the most recent 10 out of 16 publications