The E2A gene products belong to a class of helix-loop-helix (HLH) proteins, also named E-proteins. Members of the E-proteins include E12, E47, E2-2 and HEB. The DNA binding activities of the E- proteins are regulated by a distinct class of antagonistic HLH proteins, named Id gene products. The E2A proteins act at multiple stages during B cell development. In the lymphoid-primed multipotent progenitor and common lymphoid compartments, the E2A gene products act together with PU.1, EBF and Pax5 to specify a B cell fate. They maintain the expression of EBF and Pax5 in pro-B cells. In pre-B cells, the E2A proteins activate Ig: VJ gene rearrangement. In the immature-B cell compartment the E2A proteins induce receptor editing. E2A protein levels decrease upon innocuous BCR expression whereas E2A levels remain high in response to self-antigen. E2A abundance at this stage is regulated through a post-transcriptional mechanism that involves differences in protein stability. At the mature-B cell stage E2A levels are low but are elevated in response to BCR or TLR- mediated signaling, to promote class switch recombination (CSR). Here we propose to further analyze the activities of the E2A proteins at the immature- and mature-B cell stage. We would measure E12 and E47 turn-over rates in immature-B cells, expressing either an innocuous or self-reactive receptor. We would determine the individual roles of E12 and E47 at the immature-B cell stage. We would examine how the E2A proteins modulate receptor revision by identifying E2A targets in B cells expressing either an innocuous or self-reactive receptor. We would complement this analysis by performing a genome-wide screen for E2A binding sites. We would determine how the E2A proteins act with other families of transcriptional regulators to modulate down-stream target gene expression using a bioinformatics approach. We would examine the regulation and role of E-proteins in CSR. We would identify E2A binding sites, using a genome-wide screen, in naive and activated B cells. Our ultimate goal would be to identify the cis- regulatory codes that underpin the response to either tonic or auto-reactive or non-self reactive BCR- mediated signaling.
It is well known that white blood cells develop in the bone marrow from stem cells. The helix-loop- helix proteins, E12 and E47, program white blood cells to make antibodies. In the studies proposed here, we aim to determine how the helix-loop-helix proteins function in the suppression of autoimmunity.
|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; Åhsberg, 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