Bruce Richardson, M.D., Ph.D.
DNA methylation is one of the mechanisms involved in suppressing gene expression, and plays an important role in normal cellular processes such as differentiation, genomic imprinting, X chromosome inactivation, and suppression of parasitic DNA. My group examines the role of DNA methylation in the regulation of T cell function and gene expression, and characterizes the mechanisms responsible for establishing and maintaining methylation patterns. We have reported that DNA methylation plays a role in thymic differentiation, and methylation has recently been implicated in the differentiation of effector T cells as well. We have also shown that inhibiting T cell DNA methylation contributes to the development of lupus, and that changes in T cell DNA methylation patterns contribute to some of the changes in gene expression that occur with aging. Current studies characterize how hypomethylated T cells cause a lupus-like disease in animal models, and identify how signaling abnormalities cause DNA hypomethylation in T cells from lupus patients. Other studies use selective inhibitors, knockout technologies, and transfection to characterize the role of methyltransferases and demethylases in establishing and maintaining methylation patterns. Additional studies examine the regulation of these enzymes in T lymphocytes. The long term goals are to learn how to modify methylation patterns, and apply the results to pathologic states characterized by abnormal T cell DNA methylation, including autoimmunity and aging. Current research opportunities include elucidating the mechanism causing decreased ERK pathway signaling in lupus T cells, the generation of transgenic lupus models, and the effects of age on chromatin structure and gene expression.
Lu Q-J, Ray D, Gutsch D, and Richardson B. Effect of DNA methylation and chromatin structure on ITGAL expression. Blood 2002, 99:4503-4508.
Deng C, Zhang Z, Rao T, Attwood J, Lu Q, Yung R and Richardson B. Hydralazine induces autoimmunity by inhibiting ERK pathway signaling in human T cells. Arthritis Rheum 2003, 48:746-756.
Lu Q, Wu A, Ray D, Deng C, Attwood J, Hanash S, Pipkin M, Lichtenheld M, and Richardson B. DNA methylation and chromatin structure regulate T cell perforin gene expression. J Immunol 2003 170: 5118-5123.
Kaplan M, Lu Q, Wu A, Attwood J and Richardson B. Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. J Immunol 2004, 172: 3652-3561.
Oelke K, Lu Q, Richardson D, Wu A, Deng C, Hanash S, and Richardson B. Lupus T cells and T cells treated with DNA methylation inhibitors overexpress CD70 and overstimulate IgG synthesis. Arthritis Rheum 2004 50:1850-1860.
Lu Q, Wu A, Richardson B. Demethylation of the Same Promoter Sequence Increases CD70 Expression in Lupus T Cells and T Cells Treated With Lupus-Inducing Drugs. J Immunol, 2005, 174: 6212-6219.
Richardson B. Epigenetics of Autoimmunity. Nature Clinical Practice
Rheumatology 2007, 3:521-527.
Gorelik G, Fang J, Wu A, Richardson B. Impaired T cell PKCd activation
decreases ERK pathway signaling in idiopathic and hydralazine-induced
lupus. J Immunol 2007, 179:5553-5563.
Lu Q, Wu A, Tesmer L, Ray D, Yousif N and Richardson B. Demethylation
of CD40LG on the inactive X in T cells from women with lupus. J Immunol, 2007, 179:6352-6358.
Sawalha A, Jeffries M, Webb R, Lu Q, Gorelik G, Ray D, Johnson K, and
Richardson B. Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation sensitive genes. Genes and Immunity 2008, 9, 368–378.