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Series GSE143680 Query DataSets for GSE143680
Status Public on Apr 29, 2021
Title Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2.
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Mutations in the SETX gene, which encodes Senataxin, are associated with the progressive neurodegenerative diseases Ataxia with Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis 4 (ALS4). To identify the causal defect in AOA2, patient-derived cells and SETX knockouts (human and mouse) were analyzed using integrated genomic and transcriptomic approaches. We observed a genome-wide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites, resulting in changes to gene expression profiles. Senataxin loss caused increased RNA polymerase II pausing events (transcription stress) near promoters that correlated with high GCskew and R-loop accumulation at promoter-proximal regions. Notably, the chromosomal regions with gains and losses overlapped with regions of elevated transcription stress. Aberrant R-loops were resolved by transcription-coupled repair (TCR), in reactions dependent upon the Cockayne Syndrome protein CSB. We found that CSB was required for the recruitment of the TCR endonucleases XPG and XPF, and recombination factors to target and resolve transcription bubbles containing R-loops and promote genomic instability. These results show that cells derived from individuals with Ataxia with Oculomotor Apraxia 2 exhibit transcription stress giving rise to genome-wide chromosomal fragility, termed transcription stress-induced fragile sites (TSFS), in transcribed regions of the mammalian genome.
 
Overall design Examination of gene expression profiles in AOA2 and control (CTRL) lymphoblastoid cell lines by Affymetrix Human Gene 1.0 ST microarrays.
 
Contributor(s) Kanagaraj R, Chakravarty P, West SC
Citation(s)
  • Kanagaraj R, Mitter R, Kantidakis T, Edwards MM et al. Integrated genome and transcriptome analyses reveal the mechanism of genome instability in ataxia with oculomotor apraxia 2. Proc Natl Acad Sci U S A 2022 Jan 25;119(4). PMID: 35042798
Submission date Jan 14, 2020
Last update date Feb 08, 2022
Contact name Steve West
E-mail(s) stephen.west@crick.ac.uk
Organization name The Francis Crick Institute
Street address 1 Midland Road
City London
ZIP/Postal code NW1 1AT
Country United Kingdom
 
Platforms (1)
GPL6244 [HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version]
Samples (24)
GSM4272447 AOA2-P1_Replicate_1
GSM4272448 AOA2-P1_Replicate_2
GSM4272449 AOA2-P1_Replicate_3
This SubSeries is part of SuperSeries:
GSE143574 Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2
Relations
BioProject PRJNA601222

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE143680_RAW.tar 88.1 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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