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Series GSE240664 Query DataSets for GSE240664
Status Public on May 06, 2024
Title RNA-DNA hybrids formed in the absence of Senataxin drive non-coding RNA expression and protein aggregation in the nucleolus
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Neurodegeneration in the human population is often associated with loss of protein homeostasis that is driven by accumulation of specific aggregated proteins. Here we investigate whether deficiency in Senataxin, an RNA-DNA helicase associated with cerebellar ataxia and ALS, induces destabilization of intrinsically disordered proteins as we previously found with Ataxia-telangiectasia (A-T) cells and tissue. We find that Senataxin loss does generate protein aggregates but, unlike in A-T, these are associated with the nucleolus and are independent of oxidative stress and PARP activity. Non-coding RNA expression from the intergenic spacer region of ribosomal DNA is induced in the absence of Senataxin and drives the association and aggregation of many proteins known to be prone to aggregation in neurodegenerative disease. Both non-coding RNAs and protein aggregates are eliminated by overexpression of RNaseH1, implicating RNA-DNA hybrids as the key driver of these outcomes. We find that hybrids are high in the absence of Senataxin at intergenic sites, not at annotated protein-coding genes; these include sites of Senataxin binding in the genome, ribosomal DNA, and peri-centromeric regions. These findings suggest that destabilization of the proteome is driven by Senataxin loss and that RNA-DNA hybrids and non-coding RNAs play a critical role in this process.
 
Overall design R-ChIP (catalytically inactive human RNase) in wild-type and Senataxin knock out U2OS cells; RNAseq (TGIRT) in control, shSETX, and SETX knock out U2OS cells
 
Contributor(s) Wen X, Xu H, Woolley P, Conway O, Matouschek A, Lambowitz A, Paull T
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Submission date Aug 11, 2023
Last update date May 06, 2024
Contact name Tanya T. Paull
E-mail(s) tpaull@utexas.edu
Phone 5122327803
Organization name Univ. of Texas at Austin
Department Molecular Biosciences
Lab Paull
Street address 2500 Speedway MBB 2.448
City Austin
State/province TX
ZIP/Postal code 78712
Country USA
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (17)
GSM7707213 R-ChIP control rep1
GSM7707214 R-ChIP control rep2
GSM7707215 R-ChIP SETX KO rep1
Relations
BioProject PRJNA1004589

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

Supplementary file Size Download File type/resource
GSE240664_SETX_KO_HX46__47__48_TGIRT_RNAseq_CHM13T2T.bigwig 188.8 Mb (ftp)(http) BIGWIG
GSE240664_SETX_KO_HX46__47__48_TGIRT_RNAseq_CHM13T2T_negative_strand_reads.bigwig 85.9 Mb (ftp)(http) BIGWIG
GSE240664_SETX_KO_HX46__47__48_TGIRT_RNAseq_CHM13T2T_positive_strand_reads.bigwig 101.8 Mb (ftp)(http) BIGWIG
GSE240664_XW5_6_RCHIP_CHM13T2T.bigwig 580.6 Mb (ftp)(http) BIGWIG
GSE240664_XW7_8_RChIP_CHM13T2T.bigwig 537.3 Mb (ftp)(http) BIGWIG
GSE240664_shCntrl_HX37__38__39_TGIRT_RNAseq_CHM13T2T.bigwig 190.2 Mb (ftp)(http) BIGWIG
GSE240664_shCntrl_HX37__38__39_TGIRT_RNAseq_CHM13T2T_negative_strand_reads.bigwig 87.6 Mb (ftp)(http) BIGWIG
GSE240664_shCntrl_HX37__38__39_TGIRT_RNAseq_CHM13T2T_positive_strand_reads.bigwig 104.4 Mb (ftp)(http) BIGWIG
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