TREM2 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer's disease hippocampus.
TREM2 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer's disease hippocampus.
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TREM2上调与阿尔茨海默氏病海马的5-羟基环胞嘧啶富集相关。
DOI：
10.1186/s13148-016-0202-9
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发表时间：
2016
影响因子：
5.7
通讯作者：
Mendioroz M
中科院分区：
文献类型：
--
作者：
Celarain N;Sánchez-Ruiz de Gordoa J;Zelaya MV;Roldán M;Larumbe R;Pulido L;Echavarri C;Mendioroz M
最近的全基因组关联研究显示，TREM2 rs75932628-T突变与阿尔茨海默病(AD)和其他神经退行性疾病有关。然而，TREM2在散发性AD中的作用在很大程度上是未知的。我们的目的是评估AD脑中人海马区信使RNA(MRNA)的表达水平和TREM2的DNA甲基化状态。我们测量了一组神经病理证实的对照组和单纯AD患者的海马区TREM2mRNA水平，结果显示，除了β-淀粉样蛋白和磷酸化tau外，没有其他蛋白沉积。我们还通过亚硫酸氢盐克隆测序检测了TREM2转录起始点(TSS)相关区域的DNA甲基化水平，并通过5hmC DNA免疫沉淀结合实时荧光定量聚合酶链式反应(Real-time qPCR)测量了TREM2不同区域的5-羟甲基胞嘧啶(5hmC)的含量，从而进一步扩大了研究范围。AD组大鼠海马区TREM2mRNA的表达水平是对照组的3.4倍(p = 1.1E-05)。有趣的是，AD组TREM2甲基化水平高于对照组(76.2% ± 15.5vs57.9% ± 17.1；p = 0.0016)。此外，AD海马区TREM2mRNA水平与TREM2基因体5hmC的丰度相关(r = 0.771；p = 0.005)。与对照组相比，AD患者海马区TREM2基因表达水平升高。DNA甲基化，特别是5hmC，可能参与调节AD脑内TREM2基因的表达。进一步的研究将保证深入研究5hmC在AD和其他神经退行性疾病中的作用。本文的在线版本(doi：10.1186/s131480160202-9)包含补充材料，授权用户可以使用。
Recent genome-wide association studies revealed TREM2 rs75932628-T variant to be associated with Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the role that TREM2 plays in sporadic AD is largely unknown. Our aim was to assess messenger RNA (mRNA) expression levels and DNA methylation profiling of TREM2 in human hippocampus in AD brain. We measured TREM2 mRNA levels in the hippocampus in a cohort of neuropathologically confirmed controls and pure AD cases showing no other protein deposits than β-amyloid and phosphorylated tau. We also examined DNA methylation levels in the TREM2 transcription start site (TSS)-associated region by bisulfite cloning sequencing and further extended the study by measuring 5-hydroxymethycytosine (5hmC) enrichment at different regions of TREM2 by 5hmC DNA immunoprecipitation combined with real-time qPCR. A 3.4-fold increase in TREM2 mRNA levels was observed in the hippocampus of AD cases compared to controls (p = 1.1E-05). Interestingly, TREM2 methylation was higher in AD cases compared to controls (76.2 % ± 15.5 versus 57.9 % ± 17.1; p = 0.0016). Moreover, TREM2 mRNA levels in the AD hippocampus correlated with enrichment in 5hmC at the TREM2 gene body (r = 0.771; p = 0.005). TREM2 mRNA levels are increased in the human hippocampus in AD cases compared to controls. DNA methylation, and particularly 5hmC, may be involved in regulating TREM2 mRNA expression in the AD brain. Further studies are guaranteed to investigate in depth the role of 5hmC in AD and other neurodegenerative disorders. The online version of this article (doi:10.1186/s13148-016-0202-9) contains supplementary material, which is available to authorized users.