Regulation of RANTES expression in T lymphocytes

Division Of Basic Sciences - Nci

Investigators

Abstract

RANTES is a chemokine expressed 3-5 days after T cell activation. Our analysis of the RANTES promoter revealed that the transcription factor KLF13 is the major activator of RANTES expression in T cells, while rel proteins are the major inducers of the immediate increase in RANTES observed in other cell types such as fibroblasts and monocytes. Kinetic analysis of the RANTES promoter for 7 days after T cell activation showed that a variety of transcription factors move on and off the promoter over time and that phosphorylation, acetylation, and deacetylation are all important for RANTES transcription. To study more closely the role of KLF13 in vivo, mice in which the RANTES gene was disrupted were generated. Using DNA microarrays comparing wild type and KLF13 knockout animals, we found that KLF13 is involved in the transcriptional regulation of many genes. For example KLF13 is a negative regulator of BCLXL, a potent regulator of apoptosis. In August 2007, my group relocated from Stanford University to the NCI. Thus, during the past year we have equipped the laboratory and hired key personnel. We began experiments in October and are actively pursuing studies in the following areas: 1. Use the KLF13 knockout mice to identify other genes regulated by KLF13 and to evaluate these animals in animal models of human disease. 2. Identify promoters associated with KLF13 in human lymphocytes using chromatin immunoprecipitation assays and ChIP-Seq, which combines chromatin immunoprecipitation with ultra high-throughput massively parallel sequencing. These studies are aimed at designing new therapeutics for human diseases as diverse as cancer, tuberculosis, malaria, AIDS, and autoimmune diseases including diabetes, rheumatoid arthritis, and mutliple sclerosis.