Professor of Internal Medicine
Chief, Section of Rheumatology
Ann Arbor Veteran Affairs Hospital
Epigenetic mechanisms altering T cell function in autoimmunity and aging; Molecular mechanisms causing lupus; Mechanisms predisposing women to autoimmunity, Epigenetic changes caused by environmental agents, Role of oxidative damage in epigenetic alterations.
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
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.