Find A PhysicianHome  |  Library  |  myDownstate  |  Newsroom  |  A-Z Guide  |  E-mail  |  Contact Us  |  Directions
curve gif

Department of Cell Biology Faculty

Photo of Christopher A.J. Roman

Christopher A.J. Roman, Ph.D.

Associate Professor

Director, Transgenic Mouse Facility

Tel: (718) 270-1310 • Fax: (718) 270-1699

e-mail: Christopher.Roman@downstate.edu

Lymphocyte Development; Mechanisms of Oncogenesis

Research Summary

We study transcription factors and receptors that regulate lymphocyte development and the immune response. The goal is that this research will lead to a better understanding of major human health challenges such as autoimmune and inflammatory diseases like lupus, and different forms of malignancy, such as leukemia, lymphoma, and renal cancers. Key research technologies and strategies we employ to study gene function are transgenic and knock-out mouse models, retroviral gene delivery, primary mammalian cell culture systems, somatic gene and protein inactivation, flow cytometry, and immunohistochemistry. We provide research training in immunology, molecular biology, and cancer mechanisms, with dynamic collaborations with clinical departments.

TFE3 and TFEB in the immune response and in autoimmune disease.
The major focus of the lab is to understand how the transcription factors TFE3 and TFEB participate in T and B cell function. TFE3 and TFEB are closely related to the microphthalmia transcription factor Mitf, which is well known as a master transcriptional regulator of melanocyte, mast cell, and - in conjunction with TFE3 - osteoclast development. TFE3 and TFEB are the only Mitf-related transcription factors expressed in activated lymphocytes and have been implicated in the c-kit, Wnt, and TGFβ signaling pathways in non-lymphoid cells. Despite the importance of these pathways in the immune system, the normal functions of TFE3 and TFEB in lymphocytes and other hematopoietic cell types have been obscure: germline TFEB-deficiency causes early embryonic death and TFE3 deficient mice appear normal. Moreover, TFE3 and TFEB are mutated in a subset of renal malignancies, but why their mutation is almost exclusively associated with kidney cancer is unclear. We sought to reveal their physiological importance by somatic gene and protein inactivation strategies that would address their possible functional redundancy (TFE3 and TFEB share considerable amino acid sequence similarities and identities) and bypass the embryonic lethality of germline TFEB deficiency.

By simultaneously inactivating both TFE3 and TFEB in T cells, we discovered that TFE3 and TFEB are critical activators of CD40L gene expression and thus necessary for thymus-dependent humoral immune responses in vivo (Nat Immunol. 2006 Oct;7(10):1082-91.) We are in the process of identifying other TFE3/TFEB target genes that may impact T cell development and function, and are broadening and intensifying this research to define their role in other T cell subsets and B cells: we are especially interested in exploring how they modulate host responses to infection, in particular those dependent on CD8 T cells and TGFβ -dependent T cell populations.

The identification of TFE3 and TFEB as regulators of CD40L expression has very important implications with respect to better defining the molecular basis of abnormal CD40L expression by lymphocytes in multiple autoimmune diseases like systemic lupus erythematosus. This information may lead to design of new treatment strategies and new biomarkers for disease. We are now studying the relationship of TFE3 and TFEB to abnormal CD40L expression in human lupus lymphocytes in collaboration with Dr. Ellen Ginzler, Chief of Rheumatology, who runs the SUNY-Downstate Lupus Cohort.

TFE3 and TFEB function in renal and myeloid cells.
In parallel, we are interested in defining TFE3's and TFEB's role in other cell types, such as in the kidney, where they are involved in malignancy. We discovered that TFE3 and TFEB are LIF-responsive transcriptional activators of E-cadherin expression in mesenchymal cells, and when over-expressed as they are in renal tumors in which they are mutated induce expression of the Wilm's Tumor 1 (WT1) transcription factor (J Biol Chem. 2005 Aug 26;280(34):30225-35). WT1 and LIF are important for renal tubule development, and E-cadherin expression is developmentally regulated in developing renal tubules. We are very interested in exploring this pathway in renal and other lineages like dendritic and myeloid cells in which E-cadherin expression is developmentally regulated.

The regulation of early B cell development by the preBCR
A remarkable property of B and T cells is that they must assemble the genes encoding their antigen receptors via a DNA rearrangement process known as V(D)J Recombination. Although this process yields billions of genetically unique antigen receptor genes with a corresponding diversity of antigen binding specificities, the DNA recombination process itself is ignorant of the functionality of the protein that may (or may not) be encoded by the assembled gene. Because of this, at all points during lymphocyte life, the functionality of the antigen receptor is tested for structural soundness and antigen binding specificity. In B cell progenitors, the gene encoding the immunoglobulin heavy-chain (IgH) component of the antibody is rearranged first. If an IgH protein is made, its functionality is tested by whether it can form a signal transduction complex with an Ig light chain (IgL)-like molecule known as the surrogate light chain. This complex, known as the preBCR, tranduces instructive signals that activate a program of B cell differentiation and proliferation (J Immunol. 2005 Jul 1;175(1):358-66). Without a preBCR, progenitor cells do not develop; people that are genetically incapable of making a preBCR are profoundly immune deficient because they lack antibody producing B cells. Despite its importance, how the preBCR signals has been enigmatic. We showed that preBCR surface expression was not required for signal transduction, but that productive preBCR signaling is possible from intracellular, post-ER membranes such as the trans-Golgi (J Immunol. 2006 Jun 1;176(11):6862-72). Collectively, these findings called into question long-standing models positing that surface localization and extracellular ligands were vital for preBCR signaling. Future projects will ask how well intracellular preBCR signaling supports B cell development and allelic exclusion in vivo.


EDUCATION

B.A. Biochemistry, 1984 Harvard University

Ph.D. Biological Chemistry, 1991, University of California, Los Angeles

Post-Doctorate, 1992-1994 The Rockefeller Univeristy; 1994-1998 the Massachusetts Institute of Technology


RESEARCH PUBLICATIONS

  1. Huan C, Kelly ML, Steele R, Shapira I, Gottesman SR, Roman CA. Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity. Nat Immunol. 7 (10): 1082-1091. Epub 2006 Aug 27., 2006.
  2. Guloglu FB, Roman CA. Precursor B cell receptor signaling activity can be uncoupled from surface expression. J Immunol. 176 (11): 6862-72., 2006.
  3. Guloglu FB, Bajor E, Smith BP, Roman CA. The unique region of surrogate light chain component lambda5 is a heavy chain-specific regulator of precursor B cell receptor signaling. J Immunol 175 (1): 358-66., 2005.
  4. Huan C, Sashital D, Hailemariam T, Kelly ML, Roman CAJ. Renal carcinoma associated transcription factors TFE3 and TFEB are leukemia-inhibitory factor-responsive transcription activators of E-cadherin. J Biol Chem 13: 13, 2005.
  5. Fang, T., B.P. Smith, and C.A.J. Roman. (2001) "Conventional and Surrogate Light Chains Differentially Regulate Immunoglobulin mu and Dmu Heavy Chain Maturation and Surface Expression." J. Immunol.167:3846-3857

COLLABORATIVE RESEARCH PUBLICATIONS

  1. Kohlhoff a*S.A., A. Kutlin a, P. Riska b, P. M. Roblin a, C. Roman c, M. R. Hammerschlag, a In vitro models of acute and long term continuous infection of human respiratory epithelial cells with Chlamydophila pneumoniae have opposing effects on host cell apoptosis. Microb Pathog. 2007 Aug 14; [Epub ahead of print]
  2. Tian W, Nunez R, Cheng S, Ding Y, Tumang J, Lyddane C, Roman C, Liou HC. C-type lectin OCILRP2/Clr-g and its ligand NKRP1f costimulate T cell proliferation and IL-2 production. Cell Immunol. 234 (1): 39-53., 2005.
  3. Hojjati MR, Li Z, Zhou H, Tang S, Huan C, Ooi E, Lu S, Jiang XC. Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. J Biol Chem. 2005 Mar 18;280(11):10284-9. Epub 2004 Dec 6.
  4. Mokhtarian F, Huan CM, Roman C, Raine CS. Semliki Forest virus-induced demyelination and remyelination--involvement of B cells and anti-myelin antibodies. J Neuroimmunol 137 (1-2): 19-31., 2003.
  5. Donlin LT, Roman CA, Adlam M, Regelmann AG, Alexandropoulos K. Defective thymocyte maturation by transgenic expression of a truncated form of the T lymphocyte adapter molecule and Fyn substrate, Sin. J Immunol 169 (12): 6900-9., 2002.

COLLABORATORS

Susan Gottesman,
PhD, MD. Pathology; Research Collaborator

Ellen Ginzler, MD
Chief of Rheumatology, Clinical Research Collaborator


LABORATORY PERSONNEL

PRESENT

  • Chongmin Huan
    Research Scientist
  • Iglika Batova
    Post-Doctoral Scientist
  • Maria Lopez
    Graduate Student
  • Patricia Bettinger
    Graduate Student
  • Louis Semaan
    Senior Technical Support Specialist

FORMER

  • George Kardouss,
    LIU/CW Post Masters Student
  • Ewa Bajor,
    MD/PhD Student
  • Betul Guloglu,
    PhD Student
  • Chongmin Huan,
    PhD Student
  • Brendan Smith,
    MD/PhD Student
  • Iuliana Shapira,
    MD, Hematology/Oncology Resident
  • Deepa Sashital,
    MD, Hematology/Oncology Resident
  • Omar Ramadan,
    LIU/CW Post Masters Student
  • Ryan Steele,
    LIU/CW Post Masters Student
  • Shelly Bambina,
    Technical Support Specialist
  • Matthew Kelley,
    Technical Support Specialist
  • Terry Fang,
    Technical Support Specialist
  • Peter Beharrysingh,
    Transgenic Technical Specialist
  • Vadim Divilov,
    Research Intern, Hunter College/CUNY
  • Clement Choua,
    Research Intern, Baruch College/CUNY

TEACHING

College of Medicine
MS2 III: B cell Development and Activation
MS2 III: Genetic Diversification of Antigen Receptor Genes
Emerging Concepts in Medicine Cancer Biology

School of Graduate Studies/Program in Molecular and Cellular Biology
MCBI:Course Director and Lecturer:
DNA Repair; Epigenetic and Genetic Techniques;
Genetic Diversification of Antigen Receptor Genes
MCBII: Oncogenes and Tumor Suppressors
Advanced Topics: Translational Cancer Biology


SERVICE

Director, Transgenic Mouse Core Facility
Executive Committee of the College of Medicine
Executive Committee of the School of Graduate Studies
Executive Committee of the Molecular and Cellular Biology graduate program
Cancer Research Focus Group
IACUC


RELATED LINKS