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| Status |
Public on Jun 09, 2023 |
| Title |
N6-methyladenosine regulates RNA metabolism and neurodegeneration in C9ORF72-ALS/FTD [seq_polyA_RNA-decay] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
N6-methyladenosine (m6A) is the most prevalent internal mRNA modification and regulates RNA metabolism. Repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Here, we showed that m6A is downregulated in C9ORF72-ALS/FTD patient-derived iPSC-differentiated neurons and postmortem brain tissues. The global m6A hypomethylation leads to transcriptome-wide mRNA stabilization and upregulated gene expression, especially ones involved in synaptic activity and neuronal functions. The m6A modification in the C9ORF72 intron sequence preceding the expanded repeats enhances RNA degradation via the nuclear reader YTHDC1. The m6A reduction leads to increased accumulation of repeat RNA and poly-dipeptides. Moreover, the antisense RNA can also be regulated by m6A. Elevating m6A level significantly reduces both sense and antisense repeat RNA and poly-dipeptides, rescues global mRNA homeostasis, and improves survival of C9ORF72-ALS/FTD patient neurons.
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| Overall design |
The neurons at day 32 of differentiation were treated with actinomycin D to halt de novo transcription, and RNAs were collected 0, 3, and 6 hours after treatment for RNA-seq to quantify the transcriptome-wide mRNA half-life.
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| Contributor(s) |
Li Y, Dou X, He C, Sun S |
| Citation(s) |
37365312 |
| |
| Submission date |
May 23, 2022 |
| Last update date |
Sep 05, 2023 |
| Contact name |
Xiaoyang Dou |
| E-mail(s) |
xiaoyang.dou@sibcb.ac.cn
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| Organization name |
Center for Excellence in Molecular Cell Science, CAS
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| Street address |
320 Yue Yang Road
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| City |
Shanghai |
| ZIP/Postal code |
200031 |
| Country |
China |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (18)
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| This SubSeries is part of SuperSeries: |
| GSE203581 |
Globally reduced N6-methyladenosine (m6A) in C9ORF72-ALS/FTD dysregulates RNA metabolism and contributes to neurodegeneration |
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| Relations |
| BioProject |
PRJNA841495 |
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