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Disrupted processing of long pre-mRNAs and widespread RNA missplicing are components of neuronal vulnerability from loss of nuclear TDP-43

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

OTHER RELATED OMICS DATASETS IN: PRJNA141971PRJNA137005PRJNA141843PRJNA142049

ORGANISM(S): Mus musculus

PROVIDER: GSE27394 | GEO | 2011/03/03

SECONDARY ACCESSION(S): PRJNA137005

REPOSITORIES: GEO

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Disrupted processing of long pre-mRNAs and widespread RNA missplicing are components of neuronal vulnerability from loss of nuclear TDP-43 (Affymetrix)

Project description:Cross-linking and immunoprecipitation coupled with high-throughput sequencing was used to identify binding sites within 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein which when mutated causes Amyotrophic Lateral Sclerosis (ALS). Use of massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs are changed (including Fus/Tls, progranulin, and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events are detected (including in sortilin, the receptor for progranulin), following depletion of TDP-43 from adult brain with antisense oligonucleotides. RNAs whose levels are most depleted by reduction in TDP-43 are derived from genes with very long introns and which encode proteins involved in synaptic activity. Lastly, TDP-43 was found to auto-regulate its synthesis, in part by directly binding and enhancing splicing of an intron within the 3’ untranslated region of its own transcript, thereby triggering nonsense mediated RNA degradation. 6 samples of polyA-selected RNA were extracted from control-oligo and Tdp43-targeted oligo mouse striatum, and hybridized to custom splice-junction array. *Addendum Depending on the analysis software used, these CEL files may not load correctly using default parameters. This is due to the custom chip type of MJAY not being used during the array scanning step. There are three workarounds known for this problem so far. 1) If using APT, use multiple --chip-type parameters. Specifically, --chip-type mjay --chip-type MJAY --chip-type MoEx-1_0-st-v1.1sq 2) Edit the CEL file by converting to text using the APT command apt-cel-convert, then replacing the MoEx-1_0-st-v1.1sq in the DatHeader line with MJAY (all caps). 3) Edit the .pgf, .clf, and antigenomics.bmp files to use the MoEx-1_0-st-v1.1sq array instead of MJAY for the chip_type and lib_set_name options. (works on AltAnalyze software)

2011-03-03 | E-GEOD-27371 | biostudies-arrayexpress

Disrupted processing of long pre-mRNAs and widespread RNA missplicing are components of neuronal vulnerability from loss of nuclear TDP-43 (CLIP)

2011-03-03 | E-GEOD-27201 | biostudies-arrayexpress

Disrupted processing of long pre-mRNAs and widespread RNA missplicing are components of neuronal vulnerability from loss of nuclear TDP-43 (Affymetrix)

2011-03-03 | GSE27371 | GEO

Disrupted processing of long pre-mRNAs and widespread RNA missplicing are components of neuronal vulnerability from loss of nuclear TDP-43 (CLIP)

2011-03-03 | GSE27201 | GEO

Disrupted processing of long pre-mRNAs and widespread RNA missplicing are components of neuronal vulnerability from loss of nuclear TDP-43 (RNA-seq)

2011-03-03 | E-GEOD-27218 | biostudies-arrayexpress

Disrupted processing of long pre-mRNAs and widespread RNA missplicing are components of neuronal vulnerability from loss of nuclear TDP-43 (RNA-seq)

2011-03-03 | GSE27218 | GEO

Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.

Project description:We used cross-linking and immunoprecipitation coupled with high-throughput sequencing to identify binding sites in 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein that, when mutated, causes amyotrophic lateral sclerosis. Massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs were changed (including Fus (Tls), progranulin and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events were detected (including in sortilin, the receptor for progranulin) following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides. RNAs whose levels were most depleted by reduction in TDP-43 were derived from genes with very long introns and that encode proteins involved in synaptic activity. Lastly, we found that TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation.

| S-EPMC3094729 | biostudies-literature

Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs.

Project description:FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate-containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS.

| S-EPMC3586380 | biostudies-literature

Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs

Project description:This SuperSeries is composed of the following subset Series: GSE40649: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (microarray) GSE40651: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (CLIP-Seq) GSE40652: Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs (RNA-Seq) Refer to individual Series

2012-09-30 | E-GEOD-40653 | biostudies-arrayexpress

Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs

Project description:This SuperSeries is composed of the SubSeries listed below.

2012-09-30 | GSE40653 | GEO