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Regulation of constitutive and alternative messenger RNA splicing across the human transcriptome by PRPF8 is determined by 5' splice site strength

ABSTRACT: Regulation of constitutive and alternative messenger RNA splicing across the human transcriptome by PRPF8 is determined by 5' splice site strength

PROVIDER: PRJEB7544 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR657781_1.fastq.gz	Fastqsanger.gz
	ERR657781_2.fastq.gz	Fastqsanger.gz
	ERR657782_1.fastq.gz	Fastqsanger.gz
	ERR657782_2.fastq.gz	Fastqsanger.gz
	ERR657783_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Regulation of constitutive and alternative messenger RNA splicing across the human transcriptome by PRPF8 is determined by 5' splice site strength

Project description:RNA-sequencing experiments performed on control siRNA treated and PRPF8 depleted cells

2014-12-31 | E-MTAB-3021 | biostudies-arrayexpress

Regulation of constitutive and alternative mRNA splicing across the human transcriptome by PRPF8 is determined by 5' splice site strength.

Project description:BACKGROUND:Sequential assembly of the human spliceosome on RNA transcripts regulates splicing across the human transcriptome. The core spliceosome component PRPF8 is essential for spliceosome assembly through its participation in ribonucleoprotein (RNP) complexes for splice-site recognition, branch-point formation and catalysis. PRPF8 deficiency is linked to human diseases like retinitis pigmentosa or myeloid neoplasia, but its genome-wide effects on constitutive and alternative splicing remain unclear. RESULTS:Here, we show that alterations in RNA splicing patterns across the human transcriptome that occur in conditions of restricted cellular PRPF8 abundance are defined by the altered splicing of introns with weak 5' splice sites. iCLIP of spliceosome components reveals that PRPF8 depletion decreases RNP complex formation at most splice sites in exon-intron junctions throughout the genome. However, impaired splicing affects only a subset of human transcripts, enriched for mitotic cell cycle factors, leading to mitotic arrest. Preferentially retained introns and differentially used exons in the affected genes contain weak 5' splice sites, but are otherwise indistinguishable from adjacent spliced introns. Experimental enhancement of splice-site strength in mini-gene constructs overcomes the effects of PRPF8 depletion on the kinetics and fidelity of splicing during transcription. CONCLUSIONS:Competition for PRPF8 availability alters the transcription-coupled splicing of RNAs in which weak 5' splice sites predominate, enabling diversification of human gene expression during biological processes like mitosis. Our findings exemplify the regulatory potential of changes in the core spliceosome machinery, which may be relevant to slow-onset human genetic diseases linked to PRPF8 deficiency.

| S-EPMC4578845 | biostudies-literature

PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5'-splice-site selection causing tissue-specific defects

Project description:The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13, with unclear role in human splicing and tissue-specificity mechanism. We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926A>C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects. Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5’-splice site (5’SS) selection by spliceosomes, for which disruption impaired alternative splicing and weak/suboptimal 5’SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. Altered splicing efficiency, nuclear speckles organisation, and PRPF8 interaction with U6 snRNA, caused accumulation of active spliceosomes and poly(A)+ mRNAs in unique splicing clusters located at the nuclear periphery of photoreceptors. Collectively these elucidate the role of PRPF8/Brr2 regulatory mechanisms in splicing and the molecular basis of retinal disease, informing therapeutic approaches.

2024-02-16 | GSE236702 | GEO

PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects

2024-03-01 | PXD043645 | Pride

PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects

Project description:Mutations in the carboxy terminal of the core spliceosome factor PRPF8 cause autosomal dominant retinitis pigmentosa (RP) 13. Comprehensive cellular, biochemical, and molecular investigations of iPSC-derived retinal organoids, retinal pigment epithelium (RPE) and kidney organoids from four patients carrying the pathogenic PRPF8 RP type 13 c.6926A>C (p.H2309P) heterozygous missense mutation, revealed retinal tissue-specific effects including lower splicing specificity, ciliary abnormalities, altered apical-basal polarity, rod degeneration and loss of photoreceptors. The p.H2309P mutation affected the 5’ splice site recognition by PRPF8 of transcripts encoding ciliary proteins, altered spliceosome kinetics and organisation of nuclear speckles as well as PRPF8 binding to spliceosomal U6 snRNAs and snoRNAs, leading to accumulation of unspliced poly A+ mRNAs specifically in RPE cells and retinal organoids. Together these data provide the most comprehensive characterisation of splicing factor causing RP disease, providing molecular insights into the tissue specificity of pathomechanisms and informing future therapeutic approaches.

2024-02-29 | GSE235866 | GEO

E-MTAB-3021

Project description:Regulation of constitutive and alternative messenger RNA splicing across the human transcriptome by PRPF8 is determined by 5' splice site strength

2019-05-14 | E-MTAB-3021 | ExpressionAtlas

Strength training with suppressed testosterone level

Project description:Human subjects were randomized for treatment with a GnRH-analogue, Goserelin, which suppresses endogenous testosterone or placebo for 12 weeks. Strength training was performed during the last 8 weeks. The suppression of testosterone resulted in an attenuation of the normal muscle adaptation to strength training (increased muscle mass and strength). To identify molecular signals involved in the response to testosterone levels, biopsies were obtained 4 hours after the last training session and gene expression compared with Affymetrix 3' microarrays. This timepoint should capture goserelin effect on both constitutive expression, training induced changes as well as acute exercise induced (4 hours) differences in mRNA levels. Four subject from the placebo group and five subjects from the Goserelin group were compared. Total RNA from vastus lateralis mmuscle biopsies were purified and analyzed on Affymetrix HG-U133 Plus 2.0 arrays.

2014-09-30 | E-GEOD-43437 | biostudies-arrayexpress

Strength training with suppressed testosterone level

2014-09-30 | GSE43437 | GEO

PRPF8 controls alternative splicing of PIRH2 to modulate the p53 pathway and survival of human embryonic stem cells

Project description:To investigate the function of PRPF8 in survial in hESCs, we established hESC cell lines H9 in which PRPF8 has been knocked down by siRNA.We then performed gene expression profiling analysis and alternative splicing analysis using data obtained from RNA-seq of 4 different cells at two time points.

2023-12-31 | GSE213559 | GEO

Transcriptome wide identification of retained introns upon depletion of the splicing factors SNW1 or PRPF8

Project description:We identified which mRNAs are dependent on the splicing factors SNW1 or PRPF8. These factors were depleted in HeLa cells by RNAi, and the levels of intronic reads in mRNAs was compared to control RNAi. Intronic reads from polyA containing RNAs from HeLa cells and mSnw1-LAP 'rescued' cells, both depleted for endogenous SNW1, were compared. Furthermore, intronic reads from polyA containing RNAs from HeLa cells depleted for SNW1 or PRPF8 were compared to control depleted HeLa cells.

2014-09-04 | E-GEOD-61071 | biostudies-arrayexpress

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