Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis.
Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis.
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DOI：
10.1371/journal.pone.0052672
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Feldman EL
中科院分区：
文献类型：
--
作者：
Figueroa-Romero C;Hur J;Bender DE;Delaney CE;Cataldo MD;Smith AL;Yung R;Ruden DM;Callaghan BC;Feldman EL
肌萎缩性侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种涉及运动皮层、脑干和脊髓内运动神经元进行性变性的终末疾病。大多数病例是散发性的（sALS），原因不明，这表明sALS的病因可能不仅限于患者的基因型，还可能受到环境因素的影响。表观遗传修饰的改变可能在ALS的疾病发作和进展中发挥作用，因为异常的表观遗传模式可能在整个生命过程中获得。本研究的目的是确定与sALS相关的表观遗传标记。我们推测，表观遗传修饰可能会改变导致sALS发病和进展的发病相关基因的表达。使用ELISA检测，我们观察到的变化，在全球甲基化（5 mC）和羟甲基化（5 HmC）在死后的sALS脊髓，但不是在全血。通过全基因组5mC和高通量基因芯片的表达谱分析，确定sALS脊髓中位点特异性差异甲基化和表达的基因。在112个与免疫和炎症反应相关的生物学功能高度相关的基因中观察到一致的方向，高或低5mC与基因表达的平行变化（表达不足或过度）。此外，基于文献的分析确定了表观基因之间的潜在关联。甲基化组学和转录组学数据的整合成功地揭示了sALS脊髓中的甲基化变化。这项研究代表了sALS的表观遗传调控机制的初步鉴定，这可能会提高我们对sALS发病机制的理解，以确定生物标志物和新的治疗靶点。
Amyotrophic lateral sclerosis (ALS) is a terminal disease involving the progressive degeneration of motor neurons within the motor cortex, brainstem and spinal cord. Most cases are sporadic (sALS) with unknown causes suggesting that the etiology of sALS may not be limited to the genotype of patients, but may be influenced by exposure to environmental factors. Alterations in epigenetic modifications are likely to play a role in disease onset and progression in ALS, as aberrant epigenetic patterns may be acquired throughout life. The aim of this study was to identify epigenetic marks associated with sALS. We hypothesize that epigenetic modifications may alter the expression of pathogenesis-related genes leading to the onset and progression of sALS. Using ELISA assays, we observed alterations in global methylation (5 mC) and hydroxymethylation (5 HmC) in postmortem sALS spinal cord but not in whole blood. Loci-specific differentially methylated and expressed genes in sALS spinal cord were identified by genome-wide 5mC and expression profiling using high-throughput microarrays. Concordant direction, hyper- or hypo-5mC with parallel changes in gene expression (under- or over-expression), was observed in 112 genes highly associated with biological functions related to immune and inflammation response. Furthermore, literature-based analysis identified potential associations among the epigenes. Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets.
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