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| Status |
Public on Jun 19, 2020 |
| Title |
Epigenomic analysis of Parkinson’s disease neurons identifies TET2 loss as neuroprotective [PD_hMeDIP_Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by high throughput sequencing
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| Summary |
Epigenetic control of enhancers is centrally involved in modifying neuronal functions and may contribute to Parkinson's disease (PD) pathogenesis. Here, we comprehensively profile DNA methylation at enhancers genome-wide in neurons of 57 PD patients and 48 healthy individuals. There is a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly due to elevated hydroxymethylation levels. Epigenetic dysregulation of enhancers in PD converge on transcriptional abnormalities affecting neuronal signaling and immune activation pathways. In particular, PD patients exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 inactivation in a neuronal cell line enriches for cytosine modification changes that are reciprocal to those observed in PD neurons. Furthermore, Tet2 inactivation in mice fully prevents dopaminergic neuronal loss in the substantia nigra induced by prior inflammation. Tet2 loss in mice also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a novel therapeutic target for PD.
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| Overall design |
In order to determine the extent to which 5-hydroxymethylcytosine contributes to the epigenetically misregulated enhancers involved in PD, we used hMeDIP-seq to profile hydroxymethylation genome-wide in neurons of PD patients and healthy control individuals (44 individuals: 21 PD, 23 controls).
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| Contributor(s) |
Marshall L, Killinger B, Li P, Ensink E, Cui W, Li K, Gordevicius J, Weiland M, Jovinge S, Labrie V |
| Citation(s) |
32807949 |
| Submission date |
Aug 02, 2019 |
| Last update date |
Sep 18, 2020 |
| Contact name |
Lee Marshall |
| E-mail(s) |
lee.marshall@vai.org
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| Phone |
616 920 9824
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| Organization name |
Van Andel Research Institute
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| Department |
Center for Neurodegenerative Science
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| Lab |
Viviane Labrie
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| Street address |
333 Bostwick Ave NE
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| City |
Grand Rapids |
| State/province |
MI |
| ZIP/Postal code |
49503 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (45)
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| This SubSeries is part of SuperSeries: |
| GSE136010 |
Epigenomic analysis of Parkinson's disease neurons identifies TET2 loss as neuroprotective |
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| Relations |
| BioProject |
PRJNA558780 |
| SRA |
SRP217499 |
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