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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 14, 2018 |
| Title |
Parkinson-associated SNCA enhancer variants revealed by open chromatin in mouse dopamine neurons |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
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| Summary |
The progressive loss of midbrain (MB) dopaminergic (DA) neurons defines the motor features of Parkinson disease (PD) and modulation of risk by common variation in PD has been well established through GWAS. Anticipating that a fraction of PD-associated genetic variation mediates their effects within this neuronal population, we acquired open chromatin signatures of purified embryonic mouse MB DA neurons. Correlation with >2,300 putative enhancers assayed in mice reveals enrichment for MB cis-regulatory elements (CRE), data reinforced by transgenic analyses of six additional sequences in zebrafish and mice. One CRE, within intron 4 of the familial PD gene SNCA, directs reporter expression in catecholaminergic neurons of transgenic mice and zebrafish. Sequencing of this CRE in 986 PD patients and 992 controls reveals two common variants associated with elevated PD risk. To assess potential mechanisms of action, we identify proteins whose binding is impacted by these enhancer variants. Additional genotyping across the SNCA locus identifies a single PD-associated haplotype, containing the minor alleles of both of the aforementioned PD-risk variants. Our work posits a model for how common variation at SNCA may modulate PD risk and highlights the value of cell context-dependent guided searches for functional non-coding variation.
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| Overall design |
6 ATAC-seq libraries and 8 RNA-seq samples from sorted mouse Th-EGFP dopaminergic neurons collected at E15.5 from two distinct brain regions (midbrain and forebrain)
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| Contributor(s) |
McClymont SA, Hook PW, Soto AI, Reed X, Law WD, Kerans SJ, Waite EL, Briceno NJ, Thole JF, Heckman MG, Diehl NN, Wszolek ZK, Moore CD, Zhu H, Akiyama JA, Dickel DE, Visel A, Pennacchio LA, Ross OA, Beer MA, McCallion AS |
| Citation(s) |
30503521, 36747739, 36824793 |
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| Submission date |
Nov 13, 2018 |
| Last update date |
Mar 09, 2023 |
| Contact name |
Andy McCallion |
| E-mail(s) |
andy@jhmi.edu
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| Organization name |
Johns Hopkins School of Medicine
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| Department |
Institute of Genetic Medicine
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| Street address |
733 N Broadway, MRB 446
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| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21205 |
| Country |
USA |
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| Platforms (2) |
| GPL16417 |
Illumina MiSeq (Mus musculus) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (15)
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| Relations |
| BioProject |
PRJNA505267 |
| SRA |
SRP168416 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE122450_RAW.tar |
10.3 Mb |
(http)(custom) |
TAR (of TXT) |
| GSE122450_gencode.vM9_rpkm.txt.gz |
2.1 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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