Alternative splicing changes are associated with pre-birth adaptation during mouse lung development
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ABSTRACT:
PROVIDER: PRJNA732306 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14631245_1.fastq.gz | Fastqsanger.gz | |||
| SRR14631245_2.fastq.gz | Fastqsanger.gz | |||
| SRR14631246_1.fastq.gz | Fastqsanger.gz | |||
| SRR14631246_2.fastq.gz | Fastqsanger.gz | |||
| SRR14631247_1.fastq.gz | Fastqsanger.gz |
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Project description:Analysis of gene expression and alternative splicing changes in mouse lungs at different developmental time-points (E15.5, E18.5, P5, P8) was performed through RNAseq. We performed 101 nt paired-end RNAseq using HiSeq 4000 on triplicate samples. We obtained an average of 59.8 million reads per sample. The sequence reads that passed quality filters were analyzed at the transcript and at the alternative splicing events level using using D For gene expression analysis, the ~56.8 M raw reads generated per sample were uniquely mapped to the mm10 assembly and annotated to the Gencode vM14 transcriptome using TopHat2, with Bowtie2. Gene expression levels were quantified with HTSeq-count (version 0.10.0). After applying quality filters, we obtained 16,152 expressed genes for downstream analysis. For AS event-level analysis, raw reads were mapped to previously annotated AS events for the mouse reference assembly (mm10 vastdb.mm2.23.06.20) from VastDB (VastDB v2 released). Abundance of AS events in Percent spliced in (PSI) values was estimated using VAST-TOOLS. We found that most of the AS changes during alveologenesis occur at the perinatal period in genes associated with blood vessel and epithelial cell development. In particular, we found that Vegfa undergoes AS in lungs at the transition from embryonic to post-natal life, starting at the end of the embryonic period. Our results suggest provide a framework for understanding how AS changes impact on lung development during the critical period of transition to the postnatal life.
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Project description:Alternative splicing of pre-mRNA is a prominent mechanism to generate protein diversity, yet its regulation is poorly understood. Here, we demonstrate a direct role for histone modifications in alternative splicing. We find distinctive histone modification signatures which correlate with splicing outcome in a set of human genes. Modulation of histone modifications causes splice site switching. The mechanism for histone-mediated splice site selection involves a histone mark which is read by a chromatin protein, which in turn recruits a splicing regulator. These results outline an adaptor system for reading of histone marks by the pre-mRNA splicing machinery. To obtain an estimate of how many PTB-dependent alternative splicing events are regulated by SET2/MRG15-mediated recruitment of PTB, we carried out a genomewide comparative analysis of alternative splicing in hMSC cells depleted of either SETD2, MRG15 or PTB using specific siRNAs, or mock-depleted using a control siRNA.
2010-02-10 | E-GEOD-19373 | biostudies-arrayexpress
Project description:Transcription and co-transcriptional pre-mRNA splicing are kinetically coupled as shown by the widespread effects of transcription speed on alternative splicing. The molecular basis for kinetic coupling is incompletely understood, but one potential mechanism is through elongation rate dependent alternative folding pathways of the nascent pre-mRNA. To search for RNA structures in nascent pre-mRNA, we modified SPLASH (1) (Sequencing of Psoralen Crosslinked, Ligated And Selected Hybrids) for use with Chromatin Associated RNA. We applied this new method called CAR-SPLASH to cells expressing WT and slow mutant pol II and identified >3000 intragenic RNA structures of which >400 are proximal to splice sites. ASO disruption of several structures identified by CAR-SPLASH that sequester splice sites changed alternative splicing outcomes in vivo. We identified three examples of novel regulatory elements we designate “RNA kinetic switches”. ASO disruption of these structures modified alternative splicing of NISCH Exon 18 GAK Exon 7 and MEGF8 Exon 24 in a way that depended on the rate of transcription elongation. These results demonstrate that individual RNA structures can mediate kinetic coupling between transcription and pre-mRNA splicing and that nascent RNA structures can serve as targets for splice modifying ASO’s.
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Project description:Transcription and co-transcriptional pre-mRNA splicing are kinetically coupled as shown by the widespread effects of transcription speed on alternative splicing. The molecular basis for kinetic coupling is incompletely understood, but one potential mechanism is through elongation rate dependent alternative folding pathways of the nascent pre-mRNA. To search for RNA structures in nascent pre-mRNA, we modified SPLASH (1) (Sequencing of Psoralen Crosslinked, Ligated And Selected Hybrids) for use with Chromatin Associated RNA. We applied this new method called CAR-SPLASH to cells expressing WT and slow mutant pol II and identified >3000 intragenic RNA structures of which >400 are proximal to splice sites. ASO disruption of several structures identified by CAR-SPLASH that sequester splice sites changed alternative splicing outcomes in vivo. We identified three examples of novel regulatory elements we designate “RNA kinetic switches”. ASO disruption of these structures modified alternative splicing of NISCH Exon 18 GAK Exon 7 and MEGF8 Exon 24 in a way that depended on the rate of transcription elongation. These results demonstrate that individual RNA structures can mediate kinetic coupling between transcription and pre-mRNA splicing and that nascent RNA structures can serve as targets for splice modifying ASO’s.
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Project description:Both microRNAs and alternative pre-mRNA splicing have been implicated in the development of the nervous system (NS), but functional interactions between these two pathways are poorly understood. We demonstrate that the neuron-specific microRNA miR-124a directly targets PTBP1/PTB/hnRNPI mRNA, which encodes a global repressor of alternative pre-mRNA splicing in non-neuronal cells. Among the targets of PTBP1 is a critical cassette exon in the pre-mRNA of PTBP2/nPTB/brPTB, an NS-enriched PTBP1 homolog. When this exon is skipped, PTBP2 mRNA is subject to nonsense-mediated decay. During neuronal differentiation, miR-124a reduces PTBP1 levels leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. These events culminate in the transition from non-NS to NS-specific alternative splicing patterns. We also present evidence that miR-124a plays a key role in the differentiation of progenitor cells to mature neurons. Thus, miR-124a promotes NS development at least in part by regulating an intricate network of NS-specific alternative splicing. We used microarrays to detail the global programme of gene expression of CAD cells over-expressing miR-124a-2. Keywords: treatment versus control
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Project description:Alternative pre-messenger RNA (pre-mRNA) splicing is a post-transcriptional mechanism for controlling gene expression. Splicing patterns are determined by both RNA binding proteins and nuclear pre-mRNA structure. Here, we analyze pre-mRNA splicing patterns, RNA binding sites and RNA structures near these binding sites coordinately controlled by two splicing factors, the heterogeneous nuclear ribonucleoprotein hnRNPA1 and the RNA helicase DDX5. We identified thousands of alternative pre-mRNA splicing events controlled by these factors by RNA-seq following RNA interference. Enhanced CLIP (eCLIP) on nuclear extracts was used to identify protein-RNA binding sites for both proteins in the nuclear transcriptome. We found a significant overlap between hnRNPA1 and DDX5 splicing targets and that they share many closely linked binding sites as determined by eCLIP analysis. In vivo SHAPE chemical RNA structure probing data was used to model RNA structures near several exons controlled and bound by both proteins. Both sequence motifs and in vivo UV crosslinking sites for hnRNPA1 and DDX5 were used to map binding sites in their RNA targets and often these sites flanked regions of higher chemical reactivity suggesting an organized nature to nuclear pre-mRNPs. This work provides a first glimpse into the possible RNA structures surrounding pre-mRNA splicing factor binding sites.
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Project description:Mutations in pre-mRNA processing factors (PRPFs) cause autosomal dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause retinal disease. We have generated transcriptome profiles from RP11 (PRPF31-mutated) patient-derived retinal organoids and retinal pigment epithelium (RPE), as well as Prpf31+/- mouse tissues, which revealed that disrupted alternative splicing occurred for specific splicing programmes. Mis-splicing of genes encoding pre-mRNA splicing proteins was limited to patient-specific retinal cells and Prpf31+/- mouse retinae and RPE. Mis-splicing of genes implicated in ciliogenesis and cellular adhesion was associated with severe RPE defects that include disrupted apical-basal polarity, reduced trans-epithelial resistance and phagocytic capacity, and decreased cilia length and incidence. Disrupted cilia morphology also occurred in patient-derived photoreceptors, associated with progressive degeneration and cellular stress. In situ gene-editing of a pathogenic mutation rescued protein expression and key cellular phenotypes in RPE and photoreceptors, providing proof-of-concept for future therapeutic strategies.
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Project description:Although Sm-like proteins (LSMs) form the core of U6 RNPs and function in pre-mRNA splicing, little is known regarding their regulatory role in selection of splice sites, alternative splicing (AS) and splicing efficiency in eukaryotes. The Arabidopsis SAD1 locus encodes the LSM5 protein and was defined in a genetic screen for components that regulate the expression of stress-responsive gene. To further investigate regulatory role of the protein SAD1 in pre-mRNA splicing, we performed RNA sequencing (RNA-seq) to examine the changes of the global alternative splicing (AS) among the wildtype Arabidopsis plant (C24), the mutant plant (sad1) and the sad1-overexpressed plant (SAD1-OE). Our work not only provided novel insights into the regulatory role of SAD1 or LSM proteins in splicing, but also provided new cues to improving splicing efficiency and optimizing biological functions and screening the stress-resistant plant.
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