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James Hagman PhD

Professor of Immunology
 

 

 

 

 

 

Education: MS, Microbiology, University of Washington. Ph.D., Microbiology, University of Washington
E-mail: hagmanj@NJHealth.org
Dr. Hagman's National Jewish Health webpage

Regulation of B cell development

Lymphocyte differentiation proceeds through multiple stages characterized by the expression of distinct sets of genes. Our goals include understanding how the nuclear proteins Early B cell Factor (EBF) and Pax5 (B cell-specific activator protein) regulate B lineage specification, commitment and the immune response. Early B cell Factor (EBF) is a DNA-binding protein required for B cell lymphopoiesis and for the expression of proteins essential for B cell receptor function. The absence of EBF results in a developmental blockade at a pre-pro-B cell-like stage resulting in a complete lack of functional B cells and immunoglobulins. Enforced expression of EBF in hematopoietic progenitors drives production of B lineage cells at the expense of other cell types. In the absence of upstream regulators of EBF expression (PU.1, E2A or IL-7Ra), enforced expression of EBF in progenitor cells activated transcription of B cell-specific genes. In accord with these observations, we have elucidated a central role for EBF in the specification of B lineage cells. We defined a new function of EBF as a ‘pioneer’ of epigenetic modifications necessary for gene activation. These modifications are necessary for the function of other transcriptional regulators, including Pax5. Our observations suggest a molecular basis for EBF’s role in the hierarchical network of factors necessary for B lymphopoiesis. We are currently continuing our studies by using molecular techniques and animal model systems to understand how EBF initiates the remodeling of chromatin, including demethylation and de-compaction of DNA.

Other work in our laboratory addresses functions of the transcription factor Pax5. Pax5 regulates B lineage commitment in two ways. First, it activates expression of genes that are essential for the B cell developmental program. Second, it represses the expression of other lineage programs. Together with EBF, Pax5 is essential for the rearrangement and expression of immunoglobulins and other components of the B cell receptor for antigen. We previously determined that functions of Pax5 are, in part, dependent on recruitment of Ets transcription factors to bind target genes. To better understand how these mechanisms, we are currently generating transgenic mice that will allow us to modulate the expression of Pax5 during B cell development. Other studies are using embryonic stem cell technology to introduce mutations directly into pax5 genes. These mutations are expected to impair the ability of Pax5 to modulate gene expression, and ultimately its ability to influence lineage decisions.

  • Maier, H, R Ostraat, H Gao, S Fields, SA Shinton, K Medina, T Ikawa, C Murre, H Singh, RR Hardy and J Hagman. 2004. Early B cell factor cooperates with Runx1 and mediates epigenetic changes associated with mb-1 transcription. Nature Immunol 5:1069-77. Faculty of 1000 Factor 4.8.

  • Zhang, Z, CR Espinoza, Z Yu, R Stephan, T He, GS Williams, PD Burrows, J Hagman, AJ Feeney and MD Cooper. 2006. Transcription factor Pax5 (BSAP) transactivates the RAG-mediated VH to DHJH rearrangement of immunoglobulin genes. Nature Immunol 7:616-24. Faculty of 1000 Factor 3.0.

  • Joshi, NS, W Cui, A Chandele, HK Lee, DR Urso, J Hagman, L Gapin and SM Kaech. 2007. Inflammation directs memory precursor and short-lived effector
    CD8(+) T cell fates via the graded expression of T-bet transcription factor.
    Immunity 27:281-95. Faculty of 1000 Factor 6.0.

  • Fields, S, K Ternyak, H Gao, R Ostraat, J Akerlund and J Hagman. 2008. The 'zinc knuckle' motif of EBF is required for activating B cell-specific transcription. Mol Immunol, 45:3786-96.

  • Thal, MA, TL Carvalho, T He, H-G Kim, H Gao, J Hagman and CA Klug. 2009.
    Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage. Proc Natl Acad Sci USA 106:552-7.

  • Gao, H, K Lukin, J Ramírez, S Fields, D Lopez and J. Hagman. 2009. Opposing effects of SWI/SNF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5. Proc Natl Acad Sci USA 106:11258-63.

  • Hagman, J. 2009. Pillars Commentary. Conveying the message: identification of Ig-alpha and Ig-beta as components of the B cell receptor complex. J Immunol, 183:1503-4.

  • Fitzsimmons, D, K Lukin, R Lutz, CW Garvie, C Wolberger and J Hagman. 2009.
    Highly cooperative recruitment of Ets-1 and release of autoinhibition by Pax5. J Mol Biol, 392:452-64.

  • Anderson, KR, CA Torres, K Solomon, TC Becker, CB Newgard, CV Wright, J Hagman and L Sussel. 2009. Cooperative transcriptional regulation of the essential pancreatic islet gene NeuroD1 (beta2) by Nkx2.2 and neurogenin 3.
    J Biol Chem, 284:31236-31248.

  • Ramirez, J and J Hagman. 2009. The Mi-2/NuRD complex: a critical epigenetic regulator of hematopoietic development, differentiation and cancer.
    Epigenetics, 4:532-536 (featured on cover).

  • Ramírez, J, K Lukin and J Hagman. 2010. From hematopoietic progenitors to Bcells: mechanisms of lineage restriction and commitment. Curr Opin Immunol, 22:177-184.

  • Lukin, K, S Fields, D Lopez, M Cherrier, K Ternyak, J Ramírez, AJ Feeney and J Hagman. 2010. Compound haploinsufficiencies of Ebf1 and Runx1 genes impede B cell lineage progression. Proc Natl Acad Sci USA, 107:7869-7874.

  • Lin, YC, S Jhunjhunwala, C Benner, S Heinz, E Welinder, R Mansson, M Sigvardsson, J Hagman, CA Espinoza, J Dutkowski, T Ideker, CK Glass and C Murre. 2010. Cis-regulatory codes link the transcriptional regulators and tumor suppressors E2A, FOXO-1 and EBF into common pathways. Nature Immunol, 11:635-43.

  • Hong, X, J Zang, J White, C Wang, C-H Pan, R Zhao, RC Murphy, S Dai, P Henson, JW Kappler, J Hagman, and G Zhang. 2010. Interaction of JMJD6 with single-stranded RNA. Proc Natl Acad Sci USA [Epub ahead of print].

    View of Recent Publications in PubMed