Abstract
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 DNA methylation patterns are prevalent in neurons and may affect the progression and symptoms of PD.
Highlights
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
We found that hemispheric asymmetry in the epigenome of prefrontal cortex neurons changed with aging, especially for PD patients (Fig. 4)
We found that cytosine sites relevant to hemispheric asymmetry in PD had a significant increase in SNP associations relative to all cytosine sites profiled (5.3% of cytosines related to hemispheric asymmetry in PD vs. 2.0% of background cytosines, p < 10− 15, χ2 test)
Summary
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. We identify divergent epigenetic patterns involved in hemispheric asymmetry by profiling DNA methylation in isolated prefrontal cortex neurons from control and PD brain hemispheres. The lateralization of motor symptoms results from an asymmetric pattern of neurodegeneration in the brain [4,5,6,7,8]. Epigenetic marks like DNA methylation enable dynamic regulation of gene expression throughout the life of a neuron [20, 21]. Epigenetic variation may influence asymmetrical gene expression patterns in the brain, which if pathogenic could contribute to PD
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