PABPN1 loss-of-function in oculopharyngeal muscular dystrophy primarily impacts APA-shift in muscle transcripts
Shademan, M.; Mei, H.; Ariyurek, Y.; Kloet, S.; Raz, V.
Show abstract
Alternative polyadenylation (APA) at the 3UTR of transcripts contributes to the cell transcriptome. APA is suppressed by the nuclear RNA binding protein, PABPN1. Aging-associated reduced PABPN1 levels in skeletal muscles lead to muscle wasting. Muscle weakness in oculopharyngeal muscular dystrophy (OPMD) is caused by short alanine expansion in PABPN1 exon1. The expanded PABPN1 forms nuclear aggregates, an OPMD hallmark. Whether the expanded PABPN1 affect APA and how contributes to muscle pathology is unresolved. To investigate these questions, we developed a procedure including RNA library preparation and a simple pipeline calculating APA-shift ratio as a readout for PABPN1 function. Using the mouse OPMD model we demonstrate similar results between previously published PAS utilization and APA-shift results. Studying APA-shift in two OPMD models and in OPMD patients we show that the expression of the expanded PABPN1 does not correlate with APA-shift. Instead, APA-shift is correlated with reduced expression levels of PABPN1 isoforms, amongst the isoform lacking exon1. Further we show that with our protocol APA-shift is enriched in muscle transcripts, moreover in OPMD patients. We suggest that muscle weakness in OPMD is caused by PABPN1 loss-of-function leading to APA-shift that primarily affects in muscle transcripts.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Robust genetic analysis of the X-linked anophthalmic (Ie) mouse 93%
- Estimating allele-specific expression of SNVs from 10x Genomics Single-Cell RNA-Sequencing Data 92%
- Association of common genetic variants in the CPSF7 and SDHAF2 genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier 92%
Similar papers in this journal
- Characterisation of DMPK and MBNL1 expression in cell models of Myotonic Dystrophy: A platform for drug screening 93%
- Targeted deletions in human mitochondrial DNA engineered by Type V CRISPR-Cas12a system 92%
- Oligonucleotides Targeting The Splice Acceptor Site Downstream Of A Microexon As An Innovative Therapy For Autism 91%
Similar papers in this journal
- System-level analysis of genes mutated in muscular dystrophies reveals a functional pattern associated with muscle weakness distribution 93%
- Transcriptome profiling of mouse samples using nanopore sequencing of cDNA and RNA molecules 93%
- Regulatory effects of the Uty/Ddx3y locus on neighboring chromosome Y genes and autosomal mRNA transcripts in adult mouse non-reproductive cells 93%
Similar papers in this journal
- Lamin-related congenital muscular dystrophy alters mechanical signaling and skeletal muscle growth 94%
- Postnatal protein intake as a determinant of skeletal muscle structure and function in mice - a pilot study 92%
- Defining Mechanistic Links Between the Non-Coding Variant rs17673553 in CLEC16A and Lupus Susceptibility 92%
Similar papers in this journal
- Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis 95%
- Integrated data from R405W desmin knock-in mice highlight alterations of mitochondrial function, protein quality control, and myofibrillar structure in the initial stages of myofibrillar myopathy 95%
- Late-Stage Skeletal Muscle Transcriptome in Duchenne muscular dystrophy shows a BMP4-Induced Molecular Signature 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.