role of hdac3 on p53 expression and apoptosis in t cells of patients with multiple sclerosis角色hdac3 p53表达和细胞凋亡在多发性硬化症患者的t细胞.pdfVIP

Role of HDAC3 on p53 Expression and Apoptosis in T Cells of Patients with Multiple Sclerosis 1 2 2 1 Fanglin Zhang , Yaping Shi , Lily Wang , Subramaniam Sriram * 1 Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America, 2 Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America Abstract Background: Histone deacetylase 3 (HDAC3) belongs to a family of proteins which plays an important role in protein acetylation, chromatin remodeling and transcription of genes, including those that are involved in cell proliferation and cell death. While increased expression of HDAC3 is seen in neoplastic cells, the role of HDAC3 in T cells and their role in autoimmune disease is not known. Methodology/Principal Findings: Applying Affymetrix GeneChip Human Gene 1.0 ST Array and the mixed effects model for gene set analysis, we compared gene expression profiles between multiple sclerosis (MS) patients and healthy controls (HC). Within the Apoptosis_GO gene set, the constitutive expression level of HDAC3 in peripheral blood mononuclear cell (PBMC) was significantly increased in MS patients when compared to controls. Following addition of trichostatin A (TSA), an inhibitor of HDAC3, we examined the expression of p53 by flow cytometry and p53 targeted genes by real time RT-PCR in MS and HC. Culture of PBMC with TSA resulted in increased expression of p53 in HC but not in MS patients. TSA treated T cells from MS patients also showed reduced sensitivity to apoptosis when compared to HC, which was independent of activation of p53 targeted pro-apoptotic genes. Conclusion/Significance: MS pat