Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
PLoS One. 2011 Feb 8;6(2):e16795. doi: 10.1371/journal.pone.0016795.
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 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.
组蛋白去乙酰化酶 3（HDAC3）属于蛋白质家族，在蛋白质乙酰化、染色质重塑和基因转录中发挥重要作用，包括那些参与细胞增殖和细胞死亡的基因。虽然在肿瘤细胞中观察到 HDAC3 的表达增加，但 HDAC3 在 T 细胞中的作用及其在自身免疫性疾病中的作用尚不清楚。
方法/主要发现：我们应用 Affymetrix GeneChip Human Gene 1.0 ST 阵列和基因集分析的混合效应模型，比较了多发性硬化症（MS）患者和健康对照（HC）之间的基因表达谱。在凋亡_GO 基因集中，与对照组相比，MS 患者外周血单个核细胞（PBMC）中 HDAC3 的组成型表达水平显著增加。在加入 HDAC3 抑制剂曲古抑菌素 A（TSA）后，我们通过流式细胞术检查了 MS 和 HC 中 p53 的表达，并通过实时 RT-PCR 检查了 p53 靶向基因的表达。用 TSA 培养 PBMC 导致 HC 中 p53 的表达增加，但 MS 患者中则不然。与 HC 相比，来自 MS 患者的 TSA 处理后的 T 细胞对凋亡的敏感性降低，这与 p53 靶向促凋亡基因的激活无关。
结论/意义：与对照组相比，MS 患者表现出 HDAC3 表达增加，并且 T 细胞对 TSA 诱导的凋亡相对抵抗。MS 患者 PBMC 中 HDAC3 的表达增加可能使潜在的自身反应性淋巴细胞对凋亡产生抗性，从而导致自身免疫。
