Microbiology, Immunology & Molecular Genetics | Faculty | Hong Zan, Ph.D.

 

Microbiology, Immunology & Molecular Genetics Faculty

  Research | Publications | Lab Page


Hong Zan, Ph.D.
Associate Professor

Microbiology, Immunology & Molecular Genetics
School of Medicine
University of Texas Health Science Center San Antonio

5.016V.3 - MED
Tel: (210) 567-3956
Fax: (210) 567-6612
Email: zan@uthscsa.edu

 

Personal Statement

Dr. Zan has strong and long experience in B cell immune responses, estrogen-mediated regulation of gene expression and epigenetic regulation in antibody/autoantibody responses. He has been actively involved in the study of immunoglobulin class switch DNA recombination (CSR) and somatic hypermutation (SHM) in human and mouse Ig loci, as well as plasma cell and memory B cell differentiations to the understanding of CSR and SHM.

Education

Ph.D., Cell Biology and Immunology at Shanghai Institute of Cell Biology, Chinese Academy of Sciences

Research

Keywords: B Lymphocytes

Research interests:
B lymphocytes respond to infection or immunization by diversifying the antibodies (immunoglobulin, Ig) they produce through two processes: antibody class switch DNA recombination and somatic hypermutation (SHM) of their antigen-binding regions. CSR causes a change in antibody class expression from IgM to IgG, IgA or IgE, resulting in an increased ability of the antibody to remove the pathogen. SHM, in conjunction with B cell selection, results in increases in the antigen binding ability of the antibody. Class-switched/hypermutated B cells then differentiate into plasma cells that secrete large amounts of antibodies. Both SHM and CSR are highly regulated and are effected by a two-step process: (i) DNA lesions initiated by activation-induced cytidine deaminase (AID), and (ii) lesion repair by the combined intervention of DNA replication and repair factors that include translesion DNA synthesis (TLS) polymerases. Aberrant SHM and CSR, whether due to dysregulation or off-targeting of the SHM and CSR machinery, results in diseases ranging from primary immunodeficiency, systemic or organ-specific autoimmunity, atopic IgE reactions to neoplastic transformation. In addition, epigenetic marks can “interact” with genetic programs to regulate CSR, SHM and plasma cell differentiation, thereby informing the antibody response. Epigenetic dysregulation can also result in aberrant antibody responses to exogenous antigens, such as those on viruses and bacteria, or self-antigens, such as chromatin, histones and dsDNA.

Dr. Zan is interested in the molecular mechanisms involved in immunoglobulin SHM and CSR, as well as plasma cell differentiations in antibody responses to microbial pathogens and tumoral cells. He would also like to understand how dysregulation of these B cell differentiation processes lead to the production of pathogenic autoantibodies in autoimmune diseases, such as systemic lupus and rheumatoid arthritis, and how aberrant CSR and SHM machineries lead to lymphomagenesis. Dr. Zan's lab's current research is focused on the roles of the epigenetic marks, including DNA modifications, histone acetylation and microRNA, transcription factors and DNA repair proteins in these B cell specific processes, and the regulation of these elements by genetic, hormonal and environmental factors. They also aim to establish mechanistic paradigms for inhibition of CSR, SHM and plasma cell differentiation, and, therefore, blunting of class-switched and hypermutated antibodies and autoantibodies, and atopic IgEs that mediate allergy and anaphylaxis through epigenetic modulators, including histone deacetylase inhibitors that regulate histone modification and microRNA expression.

Awards and Accomplishments

Awards:

  • 2013-2014, Arthritis National Research Foundation (ANRF) Scholar
  • 2013-2014, Kelly Braden Memorial Fellow

Services:

  • Associate Editor, Autoimmunity (publisher: Informa Healthcare) 2003-
  • Guest Editor, “Epigenetics and lupus” monographic issue, Autoimmunity 2013-2014
  • Editor, The Scientific World Journal 2011-
  • Editor, Autoimmune Diseases & Therapeutic Approaches: Open Access 2013-

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Publications

  • Zan, H. and P. Casali.  2014.  microRNA in lupus. Autoimmunity. In press. (“Epigenetics and lupus” monographic issue, Guest Editor Hong Zan)
  • Zan, H. and P. Casali.  2014.  Immunoglobulin somatic hypermutation and class switch DNA recombination.  In: Encyclopedia of Medical Immunology.  I.R. Mackay & N.L. Rose, Eds.  Springer-Verlag GmbH, Heidelberg, in press.
  • Li, G., H. Zan, Z. Xu, and P. Casali.  2013. Epigenetics in the antibody response. Trend. Immunol. 34:460-470
  • Li, G., E.J. Pone, T. Mai, T.S. Lam, D. Tran, H. Zan, Z. Xu and P. Casali.  2013.  Combinatorial histone modifications target class-switch DNA recombination to S regions. Cell Reports. 5:702-714
  • Zan, H. and P. Casali.  2013.  Regulation of Aicda expression and AID activity. Autoimmunity, 46:83-101.
  • Pone, E.J., J. Zhang, T. Mai, C.A. White, G. Li, P. Patel, A. Al-Qahtani, J. Sakakura, H. Zan, Z. Xu and P. Casali.  2012.  BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class switch DNA recombination through the non-canonical NF-kB pathway.  Nature Commun. 3:767 (1-12).
  • Xu, Z., H. Zan, E.J. Pone, T. Mai and P. Casali.  2012.  Immunoglobulin class switch DNA recombination: induction, targeting and beyond.  Nature Rev. Immunol., 12:517-531
  • Zan, H., C.A. White, L. Thomas, J. Zhang, G. Li, E.S. Yu, Z. Xu, T. Mai and P. Casali.  2012. Rev1 recruits Ung to switch regions and enhances dU glycosylation for immunoglobulin class switch DNA recombination.  Cell Reports, 2:1220-1232.
  • Zan, H., J. Zhang, A. Al-Qahtani, E.J. Pone, C.A. White, D. Lee, L. Yel, T. Mai and P. Casali.  2011.  Endonuclease G plays a role in immunoglobulin class switch DNA recombination by introducing double-strand breaks in switch regions.  Mol. Immunol. 48:610-622.
  • White, C.A., J.S. Hawkins, E.J. Pone, E.S. Yu, T. Mai, A. Al-Qahtani, H. Zan and P. Casali.  2011.  AID dysregulation on in lupus-prone MRL/Faslpr/lpr mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations: modulation by HoxC4.  Autoimmunity, 44:585-598.
  • Xu, Z., Z. Fulop, G. Wu, E.J. Pone, J. Zhang, T. Mai, L.M. Thomas, A. Al-Qahtani, C.A. White, S.-R.Park, P. Steinacker, Z. Li, J. Yates 3rd, B. Herron, M. Otto, H. Zan, H. Fu and P. Casali. 2010. 14-3-3 adaptor proteins target S region-specific 5'-AGCT-3' motifs and recruit AID to unfold class switch DNA recombination. Nature Struct. Mol. Biol. 17:1124-1135.
  • Mai, T.*, H. Zan*, J. Zhang, J.S. Hawkins, Z. Xu and P. Casali. 2010. Estrogen receptors bind to and activate the promoter of the HoxC4 gene to potentiate HoxC4-mediated activation-induced cytosine deaminase induction, Immunoglobulin class-switch DNA recombination and somatic hypermutation. J. Biol. Chem. 285:37797-37810. (* These authors contributed equally to this work)
  • Zan, H., J. Zhang, S. Ardeshna, Z. Xu, S.R. Park and P. Casali. 2009. Lupus-prone MRL/faslpr/lpr mice display increased AID expression and extensive DNA lesions, comprising deletions and insertions, in the immunoglobulin locus: concurrent upregulation of somatic hypermutation and class switch DNA recombination. Autoimmunity. 42:89-103.
  • Park S.-R.*, H. Zan*, Z. Pal, J. Zhang, A. Al-Qhatani, E.J. Pone, Z. Xu, T. Mai and P. Casali. 2009. HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation. Naturte Immunol. 10:540-550 (*These authors contributed equally to this work)
  • Zan, H. and P. Casali.  2008.  AID- and Ung-dependent generation of resected double-strand DNA breaks in immunoglobulin class switch DNA recombination: a postcleavage role for AID.  Mol. Immunol. 46:45-61.
  • Wu, X., C.Y. Tsai, M. Patam, H. Zan, S.M. Lipkin and P. Casali.  2006.  A role for the MutL mismatch repair Mlh3 protein in immunoglobulin class switch DNA recombination and somatic hypermutation.  J. Immunol.176:5426-5437.
  • Casali, P., S. Pal, Z. Xu and H. Zan.  2006.  DNA repair in antibody somatic hypermutation.  Trends Immunol. 27:313-321.
  • Zan, H., N. Shima, Z. Xu, A. Al-Qahtani, A.J. Evinger, III, Y. Zhong, J.C. Schimenti and P. Casali. 2005.  The translesion DNA polymerase q plays a dominant role in immunoglobulin gene somatic hypermutation.  EMBO J. 24:3757-3769.
  • Casali, P. and H. Zan. 2004. Class switching and Myc translocation: how does DNA break?  Nature Immunol. 5:1101-1103.
  • Zan, H., X. Wu, A. Komori, Holloman, W.K. and P. Casali. 2003. AID-dependent generation of resected double-strand DNA breaks and recruitment of Rad52/Rad51 in somatic hypermutation. Immunity. 18:727-738.
  • Gurrieri, C., P. McGuire, H. Zan, X.J. Yan, A. Cerutti, E. Albesiano, S.L. Allen, V. Vinciguerra, K.R. Rai, M. Ferrarini, P. Casali and N. Chiorazzi. 2002.  Chronic lymphocytic leukemia B cells can undergo somatic hypermutation and intraclonal immunoglobulin V(D)J gene diversification. J. Exp. Med. 196:629-639.
  • Cerutti, A., H. Zan, E.C. Kim, S. Shah, E.J. Schattner, A. Schaffer and P. Casali. 2002. Ongoing in vivo immunoglobulin class switch DNA recombination in chronic lymphocytic leukemia B cells. J. Immunol. 169:6594-6603.
  • Cerutti, A., E.C. Kim, S. Shah, E.J. Schattner, H. Zan, A. Schaffer and P. Casali. 2001. Dysregulation of CD30+ T cells by leukemia impairs isotype switching in normal B cells.  Nature Immunol. 2:150-156
  • Zan, H., A. Komori, Z. Li, A. Cerutti, A. Schaffer, A.F. Flajnik, M. Diaz and P. Casali. 2001.  The translesion DNA polymerase z plays a major role in Ig and bcl-6 somatic hypermutation. Immunity 14:643-653
  • Cerutti, A., A. Schaffer, R.G. Goodwin, S. Shah, H. Zan, S. Ely and P. Casali. 2000.  Engagement of CD153 (CD30 ligand) by CD30+ T cells inhibits class switch DNA recombination and antibody production in human IgD+ IgM+ B cells. J. Immunol.  165:786-794
  • Zan, H., Z. Li, K. Yamaji, P. Dramitinos, A. Cerutti, and P. Casali. 2000.  B cell receptor engagement and T cell contact induce Bcl-6 somatic hypermutation in human B cells: identity with Ig hypermutation.  J. Immunol.  165:830-839
  • Zan, H., A. Cerutti, P. Dramitinos, A. Schaffer, Z. Li and P. Casali. 1999.  Induction of Ig somatic hypermutation and class switching in a human monoclonal IgM+IgD+ B cell line in vitro: definition of the requirements and modalities of hypermutation. J. Immunol. 162:3437-3447
  • Schaffer, A., A. Cerutti, S. Shah, H. Zan and P. Casali. 1999.  The evolutionarily conserved sequence upstream of the human Ig heavy chain S gamma 3 region is an inducible promoter: synergistic activation by CD40 ligand and IL-4 via cooperative NF-kappa B and STAT-6 binding sites.J. Immunol.  162:5327-5336
  • Zan, H., A. Cerutti, A. Schaffer, P. Dramitinos and Casali, P.  1998.  CD40 engagement triggers switching to IgA1 and IgA2 in human B cells through induction of endogenous TGF-β.  Evidence for TGF-β but not IL-10-dependent direct Sμ→Sα and sequential Sμ→Sγ, Sγ →Sα DNA recombination.  J. Immunol.161:5217-5225.
  • Cerutti, A., A. Schaffer, S. Shah, H. Zan, H.-C. Liou and P. Casali. 1998.  CD30 is a CD40-inducible molecule that negatively regulates CD40-mediated immunoglobulin class switching in non-antigen-selected human B cells.  A mechanism for preferential differentiation of antigen selected germinal center B cells.  Immunity 9:247-256.
  • Cerutti, A., H. Zan, A. Schaffer, L. Bergsagel, N. Harindranath, E. E. Max and P. Casali. 1998.  CD40 Ligand and appropriate cytokines induce switching to IgG, IgA, and IgE, and coordinated germinal center and plasmacytoid phenotypic differentiation in a human monoclonal IgM+IgD+ B cell line.  J. Immunol. 160:2145-2157.

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Lab Members

  Lab Rooms: 5.037V   Lab Phone: (210) 567-3957