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| Status |
Public on Aug 23, 2024 |
| Title |
Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Dysregulation of RNA processing contributes to neurodegenerative diseases, especially amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common cause of both FTD and ALS (C9-FTD/ALS), characterized with aberrant repeat RNA foci in the nucleus and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions in the cytoplasm. Here we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon-skipping and intron retention in human iPSC-derived neurons. Similar alternative splicing changes can be found in patient postmortem tissues. This work identified novel molecular mechanism of global RNA splicing defects by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.
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| Overall design |
To investigate nuclear speckle dysfuntion induced RNA splicing change in human neurons, we knockdown nuclear speckle essential components SON and SRRM2 by transduction with SON ans SRRM2 shRNA in human iPSC-derived i3Neurons.
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| Contributor(s) |
Wu R, Ye Y, Dong D, Li Y, Sun S |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Nov 21, 2023 |
| Last update date |
Aug 23, 2024 |
| Contact name |
Shuying Sun |
| Organization name |
jhmi
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| Street address |
720 Rutland Ave, Ross551
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| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21205 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (15)
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| GSM7913028 |
i3N, shSON rep1 |
| GSM7913029 |
i3N, shSON rep2 |
| GSM7913030 |
i3N, shSON rep3 |
| GSM7913031 |
i3N, shSRRM2 rep1 |
| GSM7913032 |
i3N, shSRRM2 rep2 |
| GSM7913033 |
i3N, shSRRM2 rep3 |
| GSM8414921 |
i3N, iGC2 rep1 |
| GSM8414922 |
i3N, iGC2 rep2 |
| GSM8414923 |
i3N, iGC2 rep3 |
| GSM8414924 |
i3N, iGC186 rep1 |
| GSM8414925 |
i3N, iGC186 rep2 |
| GSM8414926 |
i3N, iGC186 rep3 |
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| Relations |
| BioProject |
PRJNA1043685 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE248404_iGC2_vs_iGC186.A3SS.MATS.JC.txt.gz |
2.5 Mb |
(ftp)(http) |
TXT |
| GSE248404_iGC2_vs_iGC186.A5SS.MATS.JC.txt.gz |
1.9 Mb |
(ftp)(http) |
TXT |
| GSE248404_iGC2_vs_iGC186.MXE.MATS.JC.txt.gz |
1.5 Mb |
(ftp)(http) |
TXT |
| GSE248404_iGC2_vs_iGC186.RI.MATS.JC.txt.gz |
1.0 Mb |
(ftp)(http) |
TXT |
| GSE248404_iGC2_vs_iGC186.SE.MATS.JC.txt.gz |
5.9 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSON_A3SS.MATS.JC.txt.gz |
2.5 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSON_A5SS.MATS.JC.txt.gz |
1.9 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSON_MXE.MATS.JC.txt.gz |
1.8 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSON_RI.MATS.JC.txt.gz |
1.0 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSON_SE.MATS.JC.txt.gz |
6.4 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSRRM2_A3SS.MATS.JC.txt.gz |
2.5 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSRRM2_A5SS.MATS.JC.txt.gz |
1.9 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSRRM2_MXE.MATS.JC.txt.gz |
1.6 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSRRM2_RI.MATS.JC.txt.gz |
1.0 Mb |
(ftp)(http) |
TXT |
| GSE248404_shScr_vs_shSRRM2_SE.MATS.JC.txt.gz |
6.1 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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