Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain
Abstract Background Parkinson’s disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dysregulation and specifically altered histone acetylation. Nevertheless,...
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| Format: | Article |
| Language: | English |
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BMC
2021-05-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-021-00450-7 |
| _version_ | 1831693121595899904 |
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| author | Lilah Toker Gia T. Tran Janani Sundaresan Ole-Bjørn Tysnes Guido Alves Kristoffer Haugarvoll Gonzalo S. Nido Christian Dölle Charalampos Tzoulis |
| author_facet | Lilah Toker Gia T. Tran Janani Sundaresan Ole-Bjørn Tysnes Guido Alves Kristoffer Haugarvoll Gonzalo S. Nido Christian Dölle Charalampos Tzoulis |
| author_sort | Lilah Toker |
| collection | DOAJ |
| description | Abstract Background Parkinson’s disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dysregulation and specifically altered histone acetylation. Nevertheless, and despite the emerging role of epigenetics in age-related brain disorders, the question of whether aberrant histone acetylation is involved in PD remains unresolved. Methods We studied fresh-frozen brain tissue from two independent cohorts of individuals with idiopathic PD (n = 28) and neurologically healthy controls (n = 21). We performed comprehensive immunoblotting to identify histone sites with altered acetylation levels in PD, followed by chromatin immunoprecipitation sequencing (ChIP-seq). RNA sequencing data from the same individuals was used to assess the impact of altered histone acetylation on gene expression. Results Immunoblotting analyses revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. ChIP-seq analysis further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data from the same individuals revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Strikingly, this decoupling was most pronounced among nuclear-encoded mitochondrial genes, corroborating the notion that impaired crosstalk between the nucleus and mitochondria is involved in the pathogenesis of PD. Our findings independently replicated in the two cohorts. Conclusions Our findings strongly suggest that aberrant histone acetylation and altered transcriptional regulation are involved in the pathophysiology of PD. We demonstrate that PD-associated genes are particularly prone to epigenetic dysregulation and identify novel epigenetic signatures associated with the disease. |
| first_indexed | 2024-12-20T12:06:52Z |
| format | Article |
| id | doaj.art-9fc79b5444a44fc3bd31f3e48ea449ed |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-20T12:06:52Z |
| publishDate | 2021-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-9fc79b5444a44fc3bd31f3e48ea449ed2022-12-21T19:41:21ZengBMCMolecular Neurodegeneration1750-13262021-05-0116112010.1186/s13024-021-00450-7Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brainLilah Toker0Gia T. Tran1Janani Sundaresan2Ole-Bjørn Tysnes3Guido Alves4Kristoffer Haugarvoll5Gonzalo S. Nido6Christian Dölle7Charalampos Tzoulis8Neuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University HospitalNeuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University HospitalNeuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University HospitalNeuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University HospitalThe Norwegian Centre for Movement Disorders and Department of Neurology, Stavanger University HospitalNeuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University HospitalNeuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University HospitalNeuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University HospitalNeuro-SysMed Center of Excellence for Clinical Research in Neurological Diseases, Department of Neurology, Haukeland University HospitalAbstract Background Parkinson’s disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dysregulation and specifically altered histone acetylation. Nevertheless, and despite the emerging role of epigenetics in age-related brain disorders, the question of whether aberrant histone acetylation is involved in PD remains unresolved. Methods We studied fresh-frozen brain tissue from two independent cohorts of individuals with idiopathic PD (n = 28) and neurologically healthy controls (n = 21). We performed comprehensive immunoblotting to identify histone sites with altered acetylation levels in PD, followed by chromatin immunoprecipitation sequencing (ChIP-seq). RNA sequencing data from the same individuals was used to assess the impact of altered histone acetylation on gene expression. Results Immunoblotting analyses revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. ChIP-seq analysis further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data from the same individuals revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Strikingly, this decoupling was most pronounced among nuclear-encoded mitochondrial genes, corroborating the notion that impaired crosstalk between the nucleus and mitochondria is involved in the pathogenesis of PD. Our findings independently replicated in the two cohorts. Conclusions Our findings strongly suggest that aberrant histone acetylation and altered transcriptional regulation are involved in the pathophysiology of PD. We demonstrate that PD-associated genes are particularly prone to epigenetic dysregulation and identify novel epigenetic signatures associated with the disease.https://doi.org/10.1186/s13024-021-00450-7H3K27EpigeneticsNeurodegenerationChIP-seqSirtuinMitochondria |
| spellingShingle | Lilah Toker Gia T. Tran Janani Sundaresan Ole-Bjørn Tysnes Guido Alves Kristoffer Haugarvoll Gonzalo S. Nido Christian Dölle Charalampos Tzoulis Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain Molecular Neurodegeneration H3K27 Epigenetics Neurodegeneration ChIP-seq Sirtuin Mitochondria |
| title | Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain |
| title_full | Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain |
| title_fullStr | Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain |
| title_full_unstemmed | Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain |
| title_short | Genome-wide histone acetylation analysis reveals altered transcriptional regulation in the Parkinson’s disease brain |
| title_sort | genome wide histone acetylation analysis reveals altered transcriptional regulation in the parkinson s disease brain |
| topic | H3K27 Epigenetics Neurodegeneration ChIP-seq Sirtuin Mitochondria |
| url | https://doi.org/10.1186/s13024-021-00450-7 |
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