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Epigenomic analysis of Parkinson's disease neurons identifies Tet2 loss as neuroprotective.
Nature Neuroscience ( IF 21.2 ) Pub Date : 2020-08-17 , DOI: 10.1038/s41593-020-0690-y
Lee L Marshall 1 , Bryan A Killinger 1, 2 , Elizabeth Ensink 1 , Peipei Li 1 , Katie X Li 1 , Wei Cui 3 , Noah Lubben 1 , Matthew Weiland 3, 4 , Xinhe Wang 1 , Juozas Gordevicius 1, 5 , Gerhard A Coetzee 1 , Jiyan Ma 1 , Stefan Jovinge 3, 4, 6 , Viviane Labrie 1, 7
Affiliation  

Parkinson’s disease (PD) pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively examine DNA methylation at enhancers, genome-wide, in neurons of patients with PD and of control individuals. We find a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. In particular, patients with PD exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 depletion in a neuronal cell model results in cytosine modification changes that are reciprocal to those observed in PD neurons. Moreover, Tet2 inactivation in mice fully prevents nigral dopaminergic neuronal loss induced by previous inflammation. Tet2 loss also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a new therapeutic target for PD.



中文翻译:

帕金森病神经元的表观基因组分析表明,Tet2 缺失具有神经保护作用。

帕金森病 (PD) 的发病机制可能涉及改变神经元功能的增强子的表观遗传控制。在这里,我们全面检查了 PD 患者和对照个体神经元中全基因组增强子的 DNA 甲基化。我们发现 PD 神经元中增强子的胞嘧啶修饰普遍增加,部分原因是羟甲基化水平升高。特别是,PD 患者表现出TET2的表观遗传和转录上调,TET2是胞嘧啶修饰状态的主要调节因子。神经元细胞模型中的TET2耗竭导致胞嘧啶修饰变化,这与在 PD 神经元中观察到的变化相反。此外,Tet2小鼠的失活完全防止了先前炎症引起的黑质多巴胺能神经元丢失。Tet2缺失还会减弱对炎症触发的转录免疫反应。因此,PD 神经元中增强子的广泛表观遗传失调可能部分是由增加的TET2表达介导的。降低的Tet2活性在体内具有神经保护作用,可能是 PD 的新治疗靶点。

更新日期:2020-08-17
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