Abstract
BackgroundHistone 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 FindingsApplying 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/SignificanceMS 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.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and is the most common neurological disease of the CNS affecting young adults [1]
Of the 38 differentially expressed genes in the Apoptosis_GO gene set, Histone deacetylase 3 (HDAC3) was expressed at levels that were significantly higher in MS patients when compared to healthy controls (HC) (p = 0.001)
Our study shows that MS patients, when compared to controls, have an increased expression of HDAC3 and reduced susceptibility to trichostatin A (TSA) induced apoptosis in T lymphocytes, which was associated with a lack of an increase in p53 expression in MS
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and is the most common neurological disease of the CNS affecting young adults [1]. Acetylation and deacetylation of histone proteins play a pivotal role in the epigenetic regulation in many cell types, including immune lymphocytes. HAT and HDAC use a number of non-histone proteins as substrates, including p53, NFkb and STAT [11,12,13]. These protein substrates are involved in the regulation of cellular immunity and cell proliferation. 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
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