Carol F. Webb, Ph.D.
Adjunct Professor, Departments of Microbiology & Immunology and Cell Biology, University of Oklahoma Health Sciences Center
My laboratory currently has three areas of focus. Before I came to OMRF, I discovered a protein called ARID3a, or Bright, in the white blood cells called B lymphocytes. B lymphocytes are the cells that make antibodies. Antibodies are the protective proteins that are made when individuals are immunized. ARID3a was first discovered as a protein that helps regulate antibody production. However, we now know that it plays important roles in many other types of cells than B lymphocytes. Each of our projects is focused on understanding what ARID3a does in different kinds of cells.
One of our projects involves studying how ARID3a contributes to autoimmune disease. Lupus is an autoimmune disease that results in abnormal antibody production. We now know that many patients with lupus have increased amounts of ARID3a in their B lymphocytes. A major goal of my lab is to learn why ARID3a is over-expressed in blood cells from lupus patients. We hope that these results eventually will lead to better treatments for people with lupus.
The second major project in my lab involves adult stem cells. To our surprise, we discovered a number of years ago, that mice lacking ARID3a have adult tissues that can be induced to develop into other cell types. For example, skin cells could be induced to become cells that look more like nerve cells. This process is called reprogramming and is the basis for exciting new research in regenerative medicine. We do not understand how ARID3a levels cause changes in cells that allow them to be manipulated to make other cell types. Our current research focuses on learning how ARID3a can be used in regenerative medicine studies. This exciting area of research may eventually lead to new therapies for people with damaged tissues.
Finally, our lab is working with collaborators to understand how kidney development occurs. Using a special mouse cell line that doesn’t express ARID3a produced in my lab, we are learning what is necessary to form different parts of the kidney. Many diseases, including lupus and diabetes, eventually result in damage that affects kidney function. We expect the information we learn will be useful for understanding how to repair damaged kidneys.
A.B., Washington University, St. Louis, 1979
Ph.D., University of Alabama at Birmingham, 1985
Publications Committee, American Association of Immunologists, Section Editor, Journal of Immunology; Ad hoc Reviews: NIAID, NSF, Special Emphasis Panel (NIH), Gene, International Immunology, Molecular Immunology, Nucleic Acids Research, Journal of Biological Chemistry
American Association of Immunologists
American Society for Microbiology
American Association for the Advancement of Science
Joined OMRF Scientific Staff in 1990.
The DNA-binding protein ARID3a, or Bright as it was called in the mouse, has been a major focus of my lab since I helped discover as a component of a DNA-binding complex that enhances immunoglobulin heavy chain transcription. In addition, ARID3a binds matrix associated regions of DNA and can affect DNA conformations and chromatin in the immunoglobulin locus. Although we have known that ARID3a is important for hematopoietic cell functions for decades, more recent discoveries revealed unexpected suppressive functions for ARID3a in reprogramming. Currently, my lab has two major areas of study, both focused on understanding ARID3a function.
Although we showed that ARID3a is not normally expressed at all stages of B cell development, transgenic mice that over-expressed ARID3a throughout the B cell lineage produced antinuclear antigen antibodies showing an association of ARID3a with autoimmunity. We found that numbers of ARID3a+ B cells are dramatically increased in 43% of systemic lupus erythematosus patients, but not in rheumatoid arthritis patients. Intriguingly, numbers of ARID3a+ B cells were associated with increased disease activity in SLE patients, suggesting it is important to understand why ARID3a expression is increased in these patients. ARID3a was also expressed in a subset of hematopoietic progenitor stem cells in some lupus patients, indicating abnormalities in ARID3a levels in lupus may not be limited to B lymphocytes. Numbers of ARID3a+ stem progenitor cells were associated with increased proliferative potential in vitro, and increased autoantibody production in humanized mouse models. Our current experiments seek to identify mechanisms that upregulate ARID3a in normal and lupus peripheral blood cells. Ultimately, we expect to learn how ARID3a expression is linked to disease activity in lupus.
Although most of our work has focused on the role of Bright/ARID3a in cell fate changes in immune cells, multiple lines of evidence suggest that ARID3a is an important regulatory factor in reprogramming. First, we discovered that tissues from dominant negative Bright transgenic mice, and Bright knockout mice, were developmentally plastic and spontaneously formed multipotential embryoid body-like structures. In addition, shRNA knockdown of ARID3a in the human 293T cell line induced expression of the reprogramming factors Oct4, KLF4, Sox2 and cmyc, and those cells developed phenotypic characteristics of multipotent cells. Finally, Bright knockout MEFs spontaneously formed colonies that were shown to be fully pluripotent. Our new data show that ARID3a binds directly to the Oct4 promoter where it acts as a barrier for reprogramming. More recent results suggest that manipulation of ARID3a levels in human cells also leads to developmental plasticity that we predict will be useful for regenerative medicine studies. A major goal of is to investigate the mechanisms by which ARID3a contributes to reprogramming processes and epigenetic changes of defined pluripotency genes in human cells.
Inventor: Dr. Webb and Dr. Kincade
Title: Production of Pluripotent Cells through Inhibition of Bright/Arid3a Function
Date Filed: 7/10/2009
United States Patent Application: 20100008891
* Ward JM, Rose K, Montgomery C, Adrianto I, James JA, Merrill JT, Webb CF. Disease activity in lupus correlates with expression of the transcription factor AT-Rich-Interactive Domain 3a. Arthritis Rheumatol 66:3404-3412, 2014. [Abstract] EPub [Supplemental Data]
Ratliff ML, Templeton TD, Ward JM, Webb CF. The Bright side of hematopoiesis: regulatory roles of ARID3a/Bright in human and mouse hematopoiesis. Front Immunol 5:113, 2014. [Abstract]
Popowski M, Templeton TD, Lee BK, Rhee C, Li H, Miner C, Dekker JD, Orlanski S, Bergman Y, Iyer VR, Webb CF, Tucker H. Bright/Arid3A acts as a barrier to somatic cell reprogramming through direct regulation of Oct4, Sox2, and Nanog. Stem Cell Reports 2:26-35, 2014. [Article]
* Guthridge JM, Lu R, Sun H, Sun C, Wiley GB, Dominguez N, Macwana SR, Lessard CJ, Kim-Howard X, Cobb BL, Kaufman KM, Kelly JA, Langefeld CD, Adler AJ, Harley IT, Merrill JT, Gilkeson GS, Kamen DL, Niewold TB, Brown EE, Edberg JC, Petri MA, Ramsey-Goldman R, Reveille JD, Vila LM, Kimberly RP, Freedman BI, Stevens AM, Boackle SA, Criswell LA, Vyse TJ, Behrens TW, Jacob CO, Alarcon-Riquelme ME, Sivils KL, Choi J, Joo YB, Bang SY, Lee HS, Bae SC, Shen N, Qian X, Tsao BP, Scofield RH, Harley JB, Webb CF, Wakeland EK, James JA, Nath SK, Graham RR, Gaffney PM. Two Functional Lupus-Associated BLK Promoter Variants Control Cell-Type- and Developmental-Stage-Specific Transcription. Am J Hum Genet 94:586-598, 2014. [Abstract]
Oldham AL, Miner CA, Wang HC, Webb CF. The transcription factor Bright plays a role in marginal zone B lymphocyte development and autoantibody production. Mol Immunol 49:367-379, 2011. [Abstract]
Webb CF, Bryant J, Popowski M, Allred L, Kim D, Harriss J, Schmidt C, Miner CA, Rose K, Cheng HL, Griffin C, Tucker PW. The ARID family transcription factor Bright is required for both hematopoietic stem cell and B lineage development. Mol Cell Biol 31:1041-1053, 2011. [Abstract]
An G, Miner CA, Nixon JC, Kincade PW, Bryant J, Tucker PW, Webb CF. Loss of Bright/ARID3a function promotes developmental plasticity. Stem Cells 28:1560-1567, 2010. [Abstract]
Schmidt C, Kim D, Ippolito GC, Naqvi HR, Probst L, Mathur S, Rosas-Acosta G, Wilson VG, Oldham AL, Poenie M, Webb CF, Tucker PW. Signalling of the BCR is regulated by a lipid rafts-localised transcription factor, Bright. EMBO J 28:711-724, 2009. [Abstract]
Nixon JC, Ferrell S, Miner C, Oldham AL, Hochgeschwender U, Webb CF. Transgenic mice expressing dominant-negative Bright exhibit defects in B1 B cells. J Immunol 181:6913-6922, 2008. [Abstract]
Immunobiology and Cancer Research Program, MS 29
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-7999
Fax: (405) 271-2864