Genome-wide brain DNA methylation analysis suggests epigenetic reprogramming in Parkinson disease

Young, Juan I.; Sivasankaran, Sathesh K; Wang, Lily; Ali, Aleena; Mehta, Arpit; Da, Davis; Dykxhoorn, Derek M.; Petito, Carol K.; Beecham, Gary W.; Martin, Eden R.; Mash, Deborah C.; Pericak‐Vance, Margaret A.; Scott, William K.; Montine, Thomas J.; Vance, Jeffery M.

doi:10.1212/nxg.0000000000000342

Cited by 58 publications

(55 citation statements)

References 51 publications

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“…Matsumoto and collaborators found hypomethylation in the SN, but not in the anterior cingulated cortex or putamen [ 86 ]. Young and colleagues, however, detected a predominance of methylation changes in the dorsal motor nucleus of the vague in comparison to the cingulate gyrus and SN [ 130 ]. This differential methylation status has also been described for specific genes in PD samples, i.e., MAPT is hypomethylated in the putamen, but hypermethylated in the cerebellum [ 111 ].…”

Section: Epigenetic Pattern As Lbd Biomarkermentioning

confidence: 99%

“…Correspondingly, many of the genome wide significant CpGs correlate with changes in cell composition [ 122 , 133 , 142 , 143 ]. Cell composition in specific brain areas can differ between patients and controls due to degeneration and cell loss characteristic in neurodegenerative diseases [ 130 ].…”

Section: Epigenetic Pattern As Lbd Biomarkermentioning

confidence: 99%

“…As discussed above, DNA methylation in LBD has been primarily investigated within selected candidate genes [ 85 , 86 , 113 , 116 , 117 , 146 , 147 , 148 ]. However, global DNA methylation abnormalities in PD and DLB brains have been identified in several epigenome-wide studies (see Figure 2 ) [ 122 , 130 , 131 , 142 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ].…”

Section: Epigenetic Pattern As Lbd Biomarkermentioning

confidence: 99%

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Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

Urbizu

Beyer

2020

IJMS

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Lewy body disorders (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and clinical management may be difficult. The combination of genetic variation and epigenetic changes comprising gene expression-modulating DNA methylation and histone alterations modifies the phenotype, disease course, and susceptibility to disease. In this review, we summarize the results achieved in the deciphering of the LBD epigenome. To provide an appropriate context, first LBD genetics is briefly outlined. Afterwards, a detailed review of epigenetic modifications identified for LBD in human cells, postmortem, and peripheral tissues is provided. We also focus on the difficulty of identifying epigenome-related biomarker candidates and discuss the results obtained so far. Additionally, epigenetic changes as therapeutic targets, as well as different epigenome-based treatments, are revised. The number of studies focusing on PD is relatively limited and practically inexistent for DLB. There is a lack of replication studies, and some results are even contradictory, probably due to differences in sample collection and analytical techniques. In summary, we show the current achievements and directions for future research.

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Section: Epigenetic Pattern As Lbd Biomarkermentioning

confidence: 99%

Section: Epigenetic Pattern As Lbd Biomarkermentioning

confidence: 99%

Section: Epigenetic Pattern As Lbd Biomarkermentioning

confidence: 99%

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Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

Urbizu

Beyer

2020

IJMS

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“…In post-mitotic neurons, disruption of DNA methylation induces lasting changes in synaptic architecture and cellular signaling that can promote neurodegenerative processes [31][32][33]. Genome-wide studies have identified abnormalities in DNA methylation in the PD brain [34][35][36][37]. In addition, several studies of the PD brain have demonstrated a loss of DNA methylation at the αsynuclein gene promoter, which may contribute to elevated α-synuclein expression; a major PD risk factor and a main component of Lewy pathology in this disease [38][39][40][41].…”

Section: Introductionmentioning

confidence: 99%

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

Ensink

Lang

et al. 2020

Genome Biol

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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.

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“…In post-mitotic neurons, disruption of DNA methylation induces lasting changes in synaptic architecture and cellular signaling that can promote neurodegenerative processes [31][32][33] . Genomewide studies have identified abnormalities in DNA methylation in the PD brain [34][35][36][37] . In addition, several studies of the PD brain have demonstrated a loss of DNA methylation at the α-synuclein gene promoter, which may contribute to elevated α-synuclein expression [38][39][40] ; a major PD risk factor and the main component of Lewy pathology in this disease.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic contributions to hemisphere asymmetry in healthy brain, aging, and Parkinson’s disease

Li¹,

Ensink²,

Lang³

et al. 2019

Preprint

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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 determine epigenetic differences involved in hemispheric asymmetry in the healthy and the PD brain. Neurons of the healthy brain exhibit numerous hemispheric differences in DNA methylation, which affect genes implicated in neurodegenerative diseases.In PD patients, hemispheric asymmetry in DNA methylation is even greater and involves many PD risk genes. The lateralization of clinical PD symptoms involves epigenetic, transcriptional, and proteomic differences across hemispheres that affect neurodevelopment, immune activation, and synaptic transmission. During aging, healthy neurons show a progressive loss of hemispheric asymmetry in the epigenome, which is amplified in PD. For PD patients, a long disease course is associated with greater hemispheric asymmetry in neuronal epigenomes than a short disease course. Hemispheric differences in epigenetic gene regulation are prevalent in neurons and may affect the progression and symptoms of PD.

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Genome-wide brain DNA methylation analysis suggests epigenetic reprogramming in Parkinson disease

Cited by 58 publications

References 51 publications

Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

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

Epigenetic contributions to hemisphere asymmetry in healthy brain, aging, and Parkinson’s disease

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