Lu Xi, Deng Yushuang, Yu Daohai, Cao Huiming, Wang Li, Liu Li, Yu Caijia, Zhang Yuping, Guo Xiuming, Yu Gang
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China; Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
Department of Clinical Sciences, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2014 Jul 22;9(7):e103067. doi: 10.1371/journal.pone.0103067. eCollection 2014.
Epigenetic modifications, particularly histone acetylation, have been implicated in Alzheimer's disease (AD). While previous studies have suggested that histone hypoacetylation may regulate the expression of genes associated with memory and learning in AD, little is known about histone regulation of AD-related genes such as Presenilin 1(PS1) and beta-site amyloid precursor protein cleaving enzyme 1(BACE1). By utilizing neuroblastoma N2a cells transfected with Swedish mutated human amyloid precursor protein (APP) (N2a/APPswe) and wild-type APP (N2a/APPwt) as cellular models of AD, we examined the alterations of histone acetylation at the promoter regions of PS1 and BACE1 in these cells. Our results revealed that histone H3 acetylation in PS1 and BACE1 promoters is markedly increased in N2a/APPswe cells when compared to N2a/APPwt cells and control cells (vector-transfected), respectively, causing the elevated expression of PS1 and BACE1. In addition, expression of histone acetyltransferase (HAT) adenoviral E1A-associated 300-kDa protein (p300) is dramatically enhanced in N2a/APPswe cells compared to N2a/APPwt and control cells. We have further demonstrated the direct binding of p300 protein to the PS1 and BACE1 promoters in N2a/APPswe cells. The expression levels of H3 acetylation of the PS1 and BACE1 promoters and p300 protein, however, were found to be not significantly different in N2a/APPwt cells when compared to controls in our studies. Furthermore, curcumin, a natural selective inhibitor of p300 in HATs, significantly suppressed the expression of PS1 and BACE1 through inhibition of H3 acetylation in their promoter regions in N2a/APPswe cells. These findings indicated that histone acetyltransferase p300 plays a critical role in controlling the expression of AD-related genes through regulating the acetylation of their promoter regions, suggesting that p300 may represent a novel potential therapeutic target for AD.
表观遗传修饰，尤其是组蛋白乙酰化，与阿尔茨海默病（AD）有关。虽然先前的研究表明组蛋白低乙酰化可能调节AD中与记忆和学习相关基因的表达，但对于早老素1（PS1）和β-淀粉样前体蛋白裂解酶1（BACE1）等AD相关基因的组蛋白调控知之甚少。通过利用转染了瑞典突变型人淀粉样前体蛋白（APP）的神经母细胞瘤N2a细胞（N2a/APPswe）和野生型APP（N2a/APPwt）作为AD的细胞模型，我们检测了这些细胞中PS1和BACE1启动子区域组蛋白乙酰化的变化。我们的结果显示，与N2a/APPwt细胞和对照细胞（载体转染细胞）相比，N2a/APPswe细胞中PS1和BACE1启动子区域的组蛋白H3乙酰化显著增加，导致PS1和BACE1的表达升高。此外，与N2a/APPwt细胞和对照细胞相比，N2a/APPswe细胞中组蛋白乙酰转移酶（HAT）腺病毒E1A相关300 kDa蛋白（p300）的表达显著增强。我们进一步证明了N2a/APPswe细胞中p300蛋白与PS1和BACE1启动子的直接结合。然而，在我们的研究中发现，与对照相比时，N2a/APPwt细胞中PS1和BACE1启动子的H3乙酰化水平以及p300蛋白的表达水平并无显著差异。此外，姜黄素是HATs中p300的天然选择性抑制剂，通过抑制N2a/APPswe细胞中PS1和BACE1启动子区域的H3乙酰化显著抑制了PS1和BACE1的表达。这些发现表明，组蛋白乙酰转移酶p300通过调节其启动子区域的乙酰化在控制AD相关基因的表达中起关键作用，提示p300可能是AD的一个新的潜在治疗靶点。
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