title: Role of HDAC3 on p53 expression and apoptosis in T cells of patients with multiple sclerosis.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  MS patients, when compared to controls, show an increased expression of HDAC3 and relative resistance to TSA induced apoptosis in T cells. Increased expression of HDAC3 in PBMC of MS patients may render putative autoreactive lymphocytes resistance to apoptosis and thereby contribute to autoimmunity.
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Fanglin
authors.initials: F
authors.lastname: Zhang
authors.forename: Yaping
authors.initials: Y
authors.lastname: Shi
authors.forename: Lily
authors.initials: L
authors.lastname: Wang
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Sriram
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D055815:Young Adult; D000099186:Histone Deacetylase 3
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; D000099186:Histone Deacetylase 3; C012589:trichostatin A