Background Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinson’s disease (PD), but its molecular determinants are unknown. Here, we identify divergent epigenetic patterns involved in hemispheric asymmetry by profiling DNA methylation in isolated prefrontal cortex neurons from control and PD brain hemispheres. DNA methylation is fine-mapped at enhancers and promoters, genome-wide, by targeted bisulfite sequencing in two independent sample cohorts. Results We find that neurons of the human prefrontal cortex exhibit hemispheric differences in DNA methylation. Hemispheric asymmetry in neuronal DNA methylation patterns is largely mediated by differential CpH methylation, and chromatin conformation analysis finds that it targets thousands of genes. With aging, there is a loss of hemispheric asymmetry in neuronal epigenomes, such that hemispheres epigenetically converge in late life. In neurons of PD patients, hemispheric asymmetry in DNA methylation is greater than in controls and involves many PD risk genes. Epigenetic, transcriptomic, and proteomic differences between PD hemispheres correspond to the lateralization of PD symptoms, with abnormalities being most prevalent in the hemisphere matched to side of symptom predominance. Hemispheric asymmetry and symptom lateralization in PD is linked to genes affecting neurodevelopment, immune activation, and synaptic transmission. PD patients with a long disease course have greater hemispheric asymmetry in neuronal epigenomes than those with a short disease course. Conclusions Hemispheric differences in DNA methylation patterns are prevalent in neurons and may affect the progression and symptoms of PD.

中文翻译：

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人脑和帕金森病的半球不对称与神经元不同的表观遗传模式有关


背景神经元过程中的半球不对称是人脑的一个基本特征，并导致帕金森病（PD）的症状偏侧化，但其分子决定因素尚不清楚。在这里，我们通过分析来自对照和 PD 大脑半球的分离的前额叶皮层神经元的 DNA 甲基化来识别与半球不对称相关的不同表观遗传模式。通过在两个独立样本组中进行靶向亚硫酸氢盐测序，可以在全基因组范围内对增强子和启动子处的 DNA 甲基化进行精细定位。结果我们发现人类前额皮质神经元在 DNA 甲基化方面表现出半球差异。神经元 DNA 甲基化模式的半球不对称很大程度上是由差异 CpH 甲基化介导的，染色质构象分析发现它针对数千个基因。随着衰老，神经元表观基因组中的半球不对称性丧失，使得半球在晚年表观遗传上趋同。在帕金森病患者的神经元中，DNA甲基化的半球不对称性比对照组更大，并且涉及许多帕金森病风险基因。 PD半球之间的表观遗传、转录组和蛋白质组差异与PD症状的偏侧化相对应，异常在半球中最普遍，与症状优势的一侧相匹配。 PD 中的半球不对称和症状偏侧化与影响神经发育、免疫激活和突触传递的基因有关。病程长的PD患者神经元表观基因组的半球不对称性比病程短的患者更大。结论 DNA 甲基化模式的半球差异在神经元中普遍存在，可能影响 PD 的进展和症状。