Hemispheric asymmetry in the human brain and in Parkinson’s disease is linked to divergent epigenetic patterns in neurons [Bisulfite_Seq_replication_cohort]

BackgroundHemispheric 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. ResultsWe 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.ConclusionsHemispheric differences in epigenetic gene regulation are prevalent in neurons and may affect the progression and symptoms of PD.

研究背景：神经元活动中的大脑半球不对称性是人类大脑的基本特征，可驱动帕金森病（Parkinson's disease, PD）的症状偏侧化，但其分子决定因素尚不清楚。本研究通过对对照及帕金森病患者脑半球分离出的前额叶皮层神经元进行DNA甲基化谱分析，鉴定出与大脑半球不对称性相关的差异表观遗传模式。本研究采用靶向亚硫酸氢盐测序技术，在两个独立样本队列中对全基因组范围内的增强子和启动子区域进行高精度DNA甲基化定位。
研究结果：我们发现人类前额叶皮层神经元的DNA甲基化存在大脑半球差异。神经元DNA甲基化模式的大脑半球不对称性主要由差异CpH甲基化介导，染色质构象分析显示其调控数千个基因的表达。随着年龄增长，神经元表观基因组的大脑半球不对称性逐渐消失，至晚年时两侧半球的表观遗传特征趋于一致。帕金森病患者神经元的DNA甲基化半球不对称性程度高于对照组，且涉及多个帕金森病风险基因。帕金森病患者两侧脑半球的表观遗传、转录组及蛋白质组差异与帕金森病症状偏侧化相契合，异常变化在症状优势侧对应的脑半球中最为显著。帕金森病中的大脑半球不对称性与症状偏侧化，与影响神经发育、免疫激活及突触传递的基因密切相关。病程较长的帕金森病患者神经元表观基因组的半球不对称性程度高于病程较短的患者。
研究结论：神经元中基因调控的表观遗传半球差异普遍存在，且可能影响帕金森病的疾病进展与症状表现。