Transcriptomic analysis of premature termination codon mutation in the zebrafish gene psen2
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ABSTRACT:
PROVIDER: PRJNA624323 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11523561_1.fastq.gz | Fastqsanger.gz | |||
| SRR11523561_2.fastq.gz | Fastqsanger.gz | |||
| SRR11523562_1.fastq.gz | Fastqsanger.gz | |||
| SRR11523562_2.fastq.gz | Fastqsanger.gz | |||
| SRR11523563_1.fastq.gz | Fastqsanger.gz |
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Project description:PRESENILIN 2 (PSEN2) is one of the genes mutated in early onset familial Alzheimer’s disease (EOfAD). PSEN2 shares significant amino acid sequence identity with another EOfAD-related gene PRESENILIN 1 (PSEN1), and partial functional redundancy is seen between these two genes. However, the complete range of functions of PSEN1 and PSEN2 is not yet understood. In this study, we performed targeted mutagenesis of the zebrafish psen2 gene to generate a premature termination codon close downstream of the translation start with the intention of creating a null mutation. Homozygotes for this mutation, psen2S4Ter, are viable and fertile, and adults do not show any gross pigmentation defects, arguing against significant loss of γ-secretase activity. Transcripts containing the S4Ter mutation do not appear to be destabilized by nonsense-mediated decay. Forced expression in zebrafish embryos of fusions of psen2S4Ter 5’ mRNA sequences with sequence encoding green fluorescent protein (GFP) indicated that the psen2S4Ter mutation permits utilization of cryptic, novel downstream translation start codons. These likely initiate translation of N-terminally truncated Psen2 proteins that obey the “reading frame preservation rule” of PRESENILIN EOfAD mutations. Transcriptome analysis of entire brains from a 6-month-old family of wild type, heterozygous and homozygous psen2S4Ter female siblings revealed profoundly dominant effects on gene expression likely indicating changes in mitochondrial and (possibly) ribosomal function.
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Project description:Stop codon readthrough (SCR) occurs when the ribosome miscodes at a stop codon. Such readthrough events can be therapeutically desirable when a premature termination codon (PTC) is found in a critical gene. To study SCR in vivo in a genome-wide manner, we treated mammalian cells with aminoglycosides and performed ribosome profiling. We find that in addition to stimulating readthrough of PTCs, aminoglycosides stimulate readthrough of normal termination codons (NTCs) genome-wide. Stop codon identity, the nucleotide following the stop codon, and the surrounding mRNA sequence context all influence the likelihood of SCR. In comparison to NTCs, downstream stop codons in 3′UTRs are recognized less efficiently by ribosomes, suggesting that targeting of critical stop codons for readthrough may be achievable without general disruption of translation termination. Finally, we find that G418 treatment globally alters gene expression with substantial effects on translation of histone genes, selenoprotein genes, and S-adenosylmethionine decarboxylase (AMD1).
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