Altered hydroxymethylome in the substantia nigra of Parkinson's disease.
Altered hydroxymethylome in the substantia nigra of Parkinson's disease.
复制标题
帕金森病黑质中羟甲基组的改变。
DOI：
10.1093/hmg/ddac122
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发表时间：
2022
影响因子：
3.5
通讯作者：
Tang,Beisha
中科院分区：
文献类型：
--
作者：
Min,Shishi;Xu,Qian;Qin,Lixia;Li,Yujing;Li,Ziyi;Chen,Chao;Wu,Hao;Han,Junhai;Zhu,Xiongwei;Jin,Peng;Tang,Beisha
帕金森病（Parkinson's disease，PD）是第二大常见的神经退行性疾病，其发病机制与年龄、遗传和环境因素有关。DNA甲基化已被认为在神经发育和神经退行性疾病中起关键作用。5-羟甲基胞嘧啶（5 hmC）通过5-甲基胞嘧啶（5 mC）被10 - 11易位蛋白氧化而产生，并且特别富集在脑中。虽然5 hmC与多种神经系统疾病有关，但对PD患者黑质中5 hmC的改变知之甚少。为了确定PD脑样本中DNA甲基化和羟甲基化的特异性改变，我们检测了PD和阿尔茨海默病（AD）患者黑质中5 mC和5 hmC的全基因组谱。我们确定了4119差异羟甲基化区域（DhMR）和没有差异甲基化区域（DMR）在PD患者与对照组相比，死后的大脑。与AD的结果相比，这些DhMR是PD特异性的。基因本体分析显示，几个信号通路，如神经发生和神经元分化，显着丰富的PD DhMR。KEGG富集分析揭示了多种信号通路的实质性改变，包括磷脂酶D（PLD），cAMP和Rap 1。此外，使用PD果蝇模型，我们发现5 hmC调节的基因之一PLD 1调节α-突触核蛋白毒性。我们的分析表明，5 hmC可能作为一个独立的表观遗传标记，并有助于PD的发病机制。
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and aging and genetic and environmental exposure can contribute to its pathogenesis. DNA methylation has been suggested to play a pivotal role in neurodevelopment and neurodegenerative diseases. 5-hydroxymethylcytosine (5hmC) is generated through 5-methylcytosine (5mC) oxidization by ten-eleven translocation proteins and is particularly enriched in the brain. Although 5hmC has been linked to multiple neurological disorders, little is known about 5hmC alterations in the substantia nigra of patients with PD. To determine the specific alterations in DNA methylation and hydroxymethylation in PD brain samples, we examined the genome-wide profiles of 5mC and 5hmC in the substantia nigra of patients with PD and Alzheimer’s disease (ad). We identified 4119 differentially hydroxymethylated regions (DhMRs) and no differentially methylated regions (DMRs) in the postmortem brains of patients with PD compared with those of controls. These DhMRs were PD-specific when compared with the results of AD. Gene ontology analysis revealed that several signaling pathways, such as neurogenesis and neuronal differentiation, were significantly enriched in PD DhMRs. KEGG enrichment analysis revealed substantial alterations in multiple signaling pathways, including phospholipase D (PLD), cAMP and Rap1. In addition, using a PDDrosophilamodel, we found that one of the 5hmC-modulated genes,PLD1, modulated α-synuclein toxicity. Our analysis suggested that 5hmC may act as an independent epigenetic marker and contribute to the pathogenesis of PD.