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

ABSTRACT: FUS/TLS and TDP-43 are RNA/DNA-binding proteins integrally involved in amyotrophic lateral sclerosis (ALS) and frontal temporal dementia. FUS/TLS is shown to bind RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU binding motif. A characteristic sawtooth-like binding pattern is identified, supporting co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system is shown to alter levels or splicing of >970 mRNAs, most of which are distinct from the RNAs whose maturation is dependent on TDP-43. Nonetheless, only 55 RNAs are reduced upon depletion of either TDP-43 or FUS/TLS from mouse brain and human neurons differentiated from pluripotent stem cells, including mRNAs transcribed from genes with exceptionally long introns and that encode proteins essential for neuronal integrity. A subset of these is significantly lowered in FUS/TLSR521G and TDP-43G298S mutant fibroblasts and in TDP-43 aggregate-containing motor neurons in sporadic ALS, evidence pointing to a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS. Microarray of Fus/Tls in 8 week mouse brain

ORGANISM(S): Mus musculus

SUBMITTER: Gene Yeo

PROVIDER: E-GEOD-40649 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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 (CLIP-Seq)

Project description:FUS/TLS and TDP-43 are RNA/DNA-binding proteins integrally involved in amyotrophic lateral sclerosis (ALS) and frontal temporal dementia. FUS/TLS is shown to bind RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU binding motif. A characteristic sawtooth-like binding pattern is identified, supporting co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system is shown to alter levels or splicing of >970 mRNAs, most of which are distinct from the RNAs whose maturation is dependent on TDP-43. Nonetheless, only 55 RNAs are reduced upon depletion of either TDP-43 or FUS/TLS from mouse brain and human neurons differentiated from pluripotent stem cells, including mRNAs transcribed from genes with exceptionally long introns and that encode proteins essential for neuronal integrity. A subset of these is significantly lowered in FUS/TLSR521G and TDP-43G298S mutant fibroblasts and in TDP-43 aggregate-containing motor neurons in sporadic ALS, evidence pointing to a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS. CLIP of Fus/Tls in 8 week mouse brain and adult human brain

2012-09-30 | E-GEOD-40651 | biostudies-arrayexpress

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

2012-09-30 | E-GEOD-40652 | biostudies-arrayexpress

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

2012-09-30 | GSE40652 | GEO

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

2012-09-30 | GSE40651 | GEO

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

2012-09-30 | GSE40649 | 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 (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

Distinct and shared functions of ALS-associated TDP-43, FUS, and TAF15 revealed by comprehensive multi-system integrative analyses [RNA-Seq_mouse]

Project description:TDP-43, FUS, and TAF15 are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We integrate CLIP-seq and RNA Bind-N-Seq technologies to discover that TAF15 binds to ~4,900 RNAs enriched for GGUA motifs. In the mouse brain, TAF15 and FUS, but not TDP-43, exhibit strikingly similar RNA binding profiles, yet they alter the expression of distinct mRNA populations upon their individual depletions. TAF15 has a minimal role in alternative splicing and instead affects RNA turnover, consistent with an enrichment of TAF15 binding sites in 3â untranslated regions. In human stem cell-derived motor neurons, loss of both TAF15 and FUS affected mRNAs distinct from those altered by loss of either protein alone, revealing redundant roles for TAF15 and FUS in maintaining mRNA levels. Furthermore, concomitant rather than individual depletion of TAF15 and FUS more closely resembles RNA profiles of motor neurons derived from FUS R521G ALS patients or from late-stage, sporadic ALS patients. Our study reveals convergent and divergent mechanisms by which FUS, TAF15 and TDP-43 affects RNA metabolism in neurological disease. RNA-seq, CLIP-seq and arrays in mouse and human against TAF15 knockdowns This Series represents RNA-seq sample(s).

2016-07-05 | E-GEOD-77703 | biostudies-arrayexpress

Distinct and shared functions of ALS-associated TDP-43, FUS, and TAF15 revealed by comprehensive multi-system integrative analyses [array]

2016-07-05 | E-GEOD-77699 | biostudies-arrayexpress