Journal
BMC MEDICAL GENOMICS
Volume 10, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12920-017-0274-1
Keywords
RNA-seq; Cryptic exons; Splicing; TDP-43
Categories
Funding
- Medical Research Council
- Brain Research Trust PhD studentship
- Wellcome Trust [103760/Z/14/Z, FC001002]
- Francis Crick Institute from Cancer Research UK [FC001002]
- UK Medical Research Council [FC001002]
- Medical Research Council/Motor Neuron Disease Association LEW Fellowship
- NIHR UCLH BRC
- Alzheimers Research UK
- Motor Neuron Disease Association
- European Research Council
- Medical Research Council [1477245, MR/M008606/1] Funding Source: researchfish
- Motor Neurone Disease Association [Fratta/Jan15/946-795] Funding Source: researchfish
- Rosetrees Trust [M599] Funding Source: researchfish
- Wellcome Trust [103760/Z/14/Z] Funding Source: researchfish
- MRC [MR/M008606/1] Funding Source: UKRI
Ask authors/readers for more resources
Background: Reliable exon recognition is key to the splicing of pre-mRNAs into mature mRNAs. TDP-43 is an RNA-binding protein whose nuclear loss and cytoplasmic aggregation are a hallmark pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). TDP-43 depletion causes the aberrant inclusion of cryptic exons into a range of transcripts, but their extent, relevance to disease pathogenesis and whether they are caused by other RNA-binding proteins implicated in ALS/FTD are unknown. Methods: We developed an analysis pipeline to discover and quantify cryptic exon inclusion and applied it to publicly available human and murine RNA-sequencing data. Results: We detected widespread cryptic splicing in TDP-43 depletion datasets but almost none in another ALS/FTD-linked protein FUS. Sequence motif and iCLIP analysis of cryptic exons demonstrated that they are bound by TDP-43. Unlike the cryptic exons seen in hnRNP C depletion, those repressed by TDP-43 cannot be linked to transposable elements. Cryptic exons are poorly conserved and inclusion overwhelmingly leads to non-sensemediated decay of the host transcript, with reduced transcript levels observed in differential expression analysis. RNA-protein interaction data on 73 different RNA-binding proteins showed that, in addition to TDP-43, 7 specifically bind TDP-43 linked cryptic exons. This suggests that TDP-43 competes with other splicing factors for binding to cryptic exons and can repress cryptic exon inclusion. Conclusions: Our quantitative analysis pipeline confirms the presence of cryptic exons during the depletion of TDP-43 but not FUS providing new insight into to RNA-processing dysfunction as a cause or consequence in ALS/FTD.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available