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Series GSE124834 Query DataSets for GSE124834
Status Public on May 29, 2019
Title Toxic C9orf72 poly(PR) binds heterochromatin, disrupts HP1α and causes dsRNA accumulation
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary How G4C2 repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. Here, we report the first mouse model to express poly(PR), a dipeptide repeat protein synthesized from expanded G4C2 repeats. Expression of GFP-(PR)50 throughout the mouse brain yielded progressive brain atrophy, neuron5 loss, loss of poly(PR)-positive cells and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused abnormal histone methylation, lamin invaginations, decreases in HP1α expression, and disruptions of HP1α liquid phases. These aberrations of histone methylation, lamins and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element10 expression and double-stranded RNA accumulation. Thus, we uncover new mechanisms by which poly(PR) contributes to c9FTD/ALS pathogenesis.
 
Overall design Examination of transcriptome profiles using RNA-seq on 3 month old mice expressing PR and GR polypetides with an AAV expression vector. The Poly(PR) analysis consisted of 7 mice expressing AAV-GFP-(PR)50 and 4 AAV-GFP harvest-matched controls. The Poly(GR) analysis consisted of 4 mice expressing AAV-GFP-(GR)100 and 4 AAV-GFP harvest-matched controls.
 
Contributor(s) Zhang Y, Guo L, Gonzales PK, Link CD, Shorter J, Petrucelli L
Citation(s) 30765536
Submission date Jan 08, 2019
Last update date May 29, 2019
Contact name Christopher Link
Organization name University of Colorado Boulder
Department Integrative Physiology
Lab Link Lab
Street address 1725 Pleasant st
City Boulder
State/province Colorado
ZIP/Postal code 80309
Country USA
 
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (19)
GSM3555704 PR11
GSM3555705 PR16
GSM3555706 PR20
Relations
BioProject PRJNA513973
SRA SRP178051

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Supplementary file Size Download File type/resource
GSE124834_RAW.tar 5.8 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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