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Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients.
Acta Neuropathologica Communications ( IF 6.2 ) Pub Date : 2020-03-09 , DOI: 10.1186/s40478-020-00908-7
Rasmus Rydbirk 1, 2, 3, 4 , Jonas Folke 1, 3 , Florence Busato 2 , Elodie Roché 2 , Alisha Shahzad Chauhan 1, 3 , Annemette Løkkegaard 5, 6 , Anne-Mette Hejl 5 , Matthias Bode 7 , Morten Blaabjerg 7, 8 , Mette Møller 9 , Erik Hvid Danielsen 9 , Tomasz Brudek 1, 3 , Bente Pakkenberg 1, 6 , Jorg Tost 2 , Susana Aznar 1, 3
Affiliation  

Multiple system atrophy (MSA) is a rare disease with a fatal outcome. To date, little is known about the molecular processes underlying disease development. Its clinical overlap with related neurodegenerative movement disorders underlines the importance for expanding the knowledge of pathological brain processes in MSA patients to improve distinction from similar diseases. In the current study, we investigated DNA methylation changes in brain samples from 41 MSA patients and 37 healthy controls. We focused on the prefrontal cortex, a moderately affected area in MSA. Using Illumina MethylationEPIC arrays, we investigated 5-methylcytosine (5mC) as well as 5-hydroxymethylcytosine (5hmC) changes throughout the genome. We identified five significantly different 5mC probes (adj. P < 0.05), of which one probe mapping to the AREL1 gene involved in antigen presentation was decreased in MSA patients. This decrease correlated with increased 5hmC levels. Further, we identified functional DNA methylation modules involved in inflammatory processes. As expected, the decreased 5mC levels on AREL1 was concordant with increased gene expression levels of both AREL1 as well as MHC Class I HLA genes in MSA brains. We also investigated whether these changes in antigen-related processes in the brain associated with changes in peripheral mononuclear cells. Using flow cytometry on an independent cohort of MSA patients, we identified a decrease in circulating non-classical CD14+CD16++ blood monocytes, whereas T and NK cell populations were unchanged. Taken together, our results support the view of an active neuroimmune response in brains of MSA patients.

中文翻译:

多系统萎缩患者大脑中AREL1的表观遗传调控和HLA表达增加。

多系统萎缩症(MSA)是一种罕见的疾病,具有致命的后果。迄今为止,关于疾病发展的分子过程知之甚少。其与相关的神经退行性运动障碍的临床重叠强调了扩大MSA患者病理性脑过程知识以改善与类似疾病的区分的重要性。在当前的研究中,我们调查了41位MSA患者和37位健康对照者的大脑样本中DNA甲基化的变化。我们的重点是前额叶皮层,MSA的中度受影响区域。使用Illumina MethylationEPIC阵列,我们研究了整个基因组中5-甲基胞嘧啶(5mC)和5-羟甲基胞嘧啶(5hmC)的变化。我们确定了五种显着不同的5mC探针(调节P <0.05),在MSA患者中,减少了一种映射到涉及抗原呈递的AREL1基因的探针。这种降低与5hmC水平升高有关。此外,我们确定了参与炎症过程的功能性DNA甲基化模块。不出所料,AREL1上5mC水平的下降与MSA脑中AREL1以及MHC I类HLA基因的基因表达水平增加是一致的。我们还研究了大脑中抗原相关过程的这些变化是否与外周单核细胞的变化相关。在独立队列的MSA患者中使用流式细胞仪,我们发现循环中非经典CD14 + CD16 ++血液单核细胞减少,而T和NK细胞数量不变。在一起
更新日期:2020-04-22
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