RNA-seq analysis of mouse hearts over-expressing PTBP1 using an AAV9 vector
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA633802 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11811426_1.fastq.gz | Fastqsanger.gz | |||
| SRR11811426_2.fastq.gz | Fastqsanger.gz | |||
| SRR11811427_1.fastq.gz | Fastqsanger.gz | |||
| SRR11811427_2.fastq.gz | Fastqsanger.gz | |||
| SRR11811428_1.fastq.gz | Fastqsanger.gz |
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Project description:We describe an improved individual nucleotide resolution CLIP protocol (iiCLIP), which can be completed within 4 days from UV crosslinking to libraries for sequencing. For benchmarking, we directly compared PTBP1 iiCLIP libraries with the iCLIP2 protocol produced under standardised conditions with 1 million HEK293 cells, and with public eCLIP and iCLIP PTBP1 data. There are 3 PTBP1 iiCLIP libraries, 1 input iiCLIP library and 1 PTBP1 iCLIP2 library produced in this study.
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Project description:Inherited retinal disorders (IRD) have become a primary focus of gene therapy research since the success of AAV-based therapeutics (voretigene neparvovec-rzyl) for Leber congenital amaurosis type 2 (LCA2). Dozens of monogenic IRDs could be potentially treated with a similar approach using adeno-associated virus (AAV) to transfer a functional gene into the retina. Here, we present the results of design, production and in vitro testing of the AAV serotype 9 (AAV9) vector carrying the codon-optimized (co) copy of aryl hydrocarbon receptor interacting protein like-1 (AIPL1) as a possible treatment for LCA4. The pAAV-AIPL1co was able to successfully transduce retinal pigment epithelium cells (ARPE-19) and initiate expression of human AIPL1. Intriguingly, cells transduced with AAV9-AIPL1co showed much less antiviral response than AAV9-AIPL1wt (wild type AIPL1 ) transduced. RNA-sequencing (RNA-seq) analysis of trans-differentiated ARPE-19 cells transduced with AAV9-AIPL1co demonstrated the significant differences in expression of genes involved in innate immune response. In contrast, AAV9-AIPL1wt induced prominent activation of multiple interferon-stimulated genes. The key part of possible regulatory molecular mechanism is activation of dsRNA-responsive antiviral oligoadenylate synthetases, and significant increase in level of histone coding genes’ transcripts overrepresented in RNA-seq data (i.e. H1, H2A, H2B, H3 and H4). The RNA-seq data suggests that AAV9-AIPL1co exhibiting less immunogenicity than AAV9-AIPL1wt can be used for potency testing using relevant animal models to develop future therapeutics for LCA4.
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Project description:Ribosomopathies constitute a range of disabling conditions associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here we demonstrate that deletion of Polypyrimidine Tract Binding Protein 1 (PTBP1) in the hematopoietic compartment led to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 was associated with a decrease in HSC self-renewal, erythroid differentiation and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency led to splicing defects in hundreds of genes and we demonstrate that the up-regulation of a specific isoform of CDC42 could partly mimic the protein synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency was associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA binding proteins.
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Project description:Purpose: Duchenne muscular dystrophy (DMD) is typically caused by mutations that disrupt the DMD reading frame, but nonsense mutations in the 5’ part of the gene lead to the utilization of an internal ribosomal entry site (IRES) in exon 5, resulting in expression of a highly functional N-truncated dystrophin. We have developed an AAV9 vector expressing U7 small nuclear RNAs targeting DMD exon 2 and tested it in a mouse model containing a duplication of exon 2, in which skipping of both exon 2 copies results in IRES-induced expression, and skipping of only one exon 2 leads to wild-type dystrophin expression. Methods: One-time intravascular injection of an AAV9 vector expressing U7 small nuclear RNAs targeting Dmd exon 2 at either P0-P1 or at 2 months of age results in efficient exon skipping and dystrophin expression, and significant protection from functional and pathologic deficits. Results: In mice treated neonatally, dystrophin immunofluorescence reached 49-85% of normal signal intensity and 76-99% dystrophin-positive fibers, with near-complete correction of dystrophic pathology, and these beneficial effects showed no significant signs of declining for at least 6 months. RNA sequencing (RNA-Seq) and Ribosome Profiling (RPF-Seq) indicated that treatment restored a ‘non-dystrophic’ gene expression profile by reversing the direction and magnitude of differentially expressed genes previously identified in dystrophic skeletal muscle from DMD patients. The dystrophin transcript showed clearly increased RPF reads in the treated sample, indicating that the treatment specifically increased dystrophin translation. Conclusions: The results demonstrate the robustness, durability, and safety of exon 2 skipping following delivery of scAAV9.U7snRNA.ACCA, supporting its clinical use.
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