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Series GSE65973 Query DataSets for GSE65973
Status Public on Oct 15, 2015
Title RNA sequencing of mice expressing NLS-hTDP-43
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display a loss of endogenous mouse nuclear TDP-43 as well as dramatic changes in gene expression as measured by microarray. Here, we analyze RNA-sequencing data from the ∆NLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice and High Throughput Sequencing of RNA isolated by CrossLinking ImmunoPrecipitation (HITS-CLIP) data of TDP-43’s RNA binding targets to further investigate the dysregulation of gene expression in the ∆NLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3’ untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.
Overall design RNAseq of bigenic (n=4) ∆NLS-hTDP-43 and control nontransgenic (n=4) mouse cortex
Contributor(s) Amlie-Wolf A, Lee EB
Citation(s) 26510133
Submission date Feb 17, 2015
Last update date May 15, 2019
Contact name Edward Lee
Phone (215) 898-0908
Organization name University of Pennsylvania
Department Pathology and Laboratory Medicine
Lab Translational Neuropathology Research Laboratory
Street address 605B Stellar Chance Laboratories, 422 Curie Blvd
City Philadelphia
State/province PA
ZIP/Postal code 19104
Country USA
Platforms (1)
GPL9250 Illumina Genome Analyzer II (Mus musculus)
Samples (8)
GSM1611863 bigenic_RNAseq_1
GSM1611864 bigenic_RNAseq_2
GSM1611865 bigenic_RNAseq_3
BioProject PRJNA275618
SRA SRP055082

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Supplementary file Size Download File type/resource
GSE65973_NLS_deseq2_all_alluniq_vs_mmu9htdp43nls.txt.gz 864.5 Kb (ftp)(http) TXT
GSE65973_NLS_norm_counts_all.txt.gz 365.8 Kb (ftp)(http) TXT
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