Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects

Rogalska, Malgorzata; Vivori, Claudia; Valcárcel, Juan

doi:10.1038/s41576-022-00556-8

Cited by 97 publications

(73 citation statements)

References 319 publications

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“…4d). Secondly, this analysis provided support for splice site inter-communication 34,53 , with sequence properties at the 3'ss impacting on the fidelity of 5'ss splicing and to a lesser extent vice versa. Finally, we found that sequence conservation in genomic regions flanking the 5' and 3'ss had the largest effect on splicing accuracy, with higher conservation scores at both sites associated with lower mis-splicing.…”

Section: Local Sequence Conservation Is the Most Important Predictor ...mentioning

confidence: 76%

“…The recognition of the donor splice site (5'ss) and acceptor splice site (3'ss) of an intron is performed by separate components of the splicing machinery 34,47,48 . We aimed to test whether mis-splicing rates at these splice sites also differed.…”

Section: Mis-splicing Is More Common At Acceptor Than Donor Splice Sitesmentioning

confidence: 99%

“…Accurate splicing is essential for human health [21][22][23][24][25][26][27] . While mechanisms such as the nonsense-mediated decay (NMD) can mitigate the impact of spurious mRNA transcripts [28][29][30][31][32][33] , differential use of splice sites escaping this mechanisms has demonstrated widespread dysregulation in a range of diseases 34 , including Alzheimer's disease 35,36 , frontotemporal dementia 37,38 and multiple cancers [39][40][41][42] . It has recently been suggested that ageing may exacerbate splicing errors, with intron retention events and spurious splicing becoming more prevalent with age and disease incidence 43 .…”

Section: Introductionmentioning

confidence: 99%

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Splicing accuracy varies across human introns, tissues and age

García-Ruiz

Zhang²,

Rocamora-Perez³

et al. 2023

Preprint

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Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigated mis-splicing using RNA-sequencing data from ~14K control samples and 42 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that mis-splicing occurs at different rates across introns and tissues and that these splicing inaccuracies are primarily affected by the abundance of core components of the spliceosome assembly and its regulators. Using publicly available data on short-hairpin RNA-knockdowns of numerous spliceosomal components and related regulators, we found support for the importance of RNA-binding proteins in mis-splicing. We also demonstrated that age is positively correlated with mis-splicing, and it affects genes implicated in neurodegenerative diseases. This in-depth characterisation of mis-splicing can have important implications for our understanding of the role of splicing inaccuracies in human disease and the interpretation of long-read RNA-sequencing data.

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Section: Local Sequence Conservation Is the Most Important Predictor ...mentioning

confidence: 76%

Section: Mis-splicing Is More Common At Acceptor Than Donor Splice Sitesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Splicing accuracy varies across human introns, tissues and age

García-Ruiz

Zhang²,

Rocamora-Perez³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…We anticipate the option to include prior knowledge and allow the restriction of the FDR correction to sets of candidate genes to be especially useful in diagnostic strategies where DNA sequencing is routinely done as a first step and RNA-seq is used as a follow-up. As splicing-based therapeutics are on the rise (3,35), we hope FRASER 2.0 will be a useful tool for the identification of the exact aberrant splicing event for these new targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

“…The regulation of splicing is important to control isoform expression and cellular function (1)(2)(3). Defects at the level of the pre-mRNA splicing process represent a major cause of human disease.…”

Section: Introductionmentioning

confidence: 99%

Improved detection of aberrant splicing using the Intron Jaccard Index

Scheller

Lutz

Mertes

et al. 2023

Preprint

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Detection of aberrantly spliced genes is an important step in RNA-seq-based rare disease diagnostics. We recently developed FRASER, a denoising autoencoder-based method for aberrant splicing detection that outperformed alternative approaches. However, as FRASER's three splice metrics are partially redundant and tend to be sensitive to sequencing depth, we introduce here a more robust intron excision metric, the Intron Jaccard Index, that combines alternative donor, alternative acceptor, and intron retention signal into a single value. Moreover, we optimized model parameters and filter cutoffs using candidate rare splice-disrupting variants as independent evidence. On 16,213 GTEx samples, our improved algorithm called typically 10 times fewer splicing outliers while increasing the proportion of candidate rare splice-disrupting variants by 10 fold and substantially decreasing the effect of sequencing depth on the number of reported outliers. Application on 303 rare disease samples confirmed the reduction fold-change of the number of outlier calls for a slight loss of sensitivity (only 2 out of 22 previously identified pathogenic splicing cases not recovered). Altogether, these methodological improvements contribute to more effective RNA-seq-based rare diagnostics by a drastic reduction of the amount of splicing outlier calls per sample at minimal loss of sensitivity.

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CDK12‐inactivation‐induced MYC signaling causes dependency on the splicing kinase SRPK1

Liang,

Gondane,

Itkonen

2024

Molecular Oncology

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Inactivation of cyclin‐dependent kinase 12 (CDK12) characterizes an aggressive sub‐group of castration‐resistant prostate cancer (CRPC). Hyper‐activation of MYC transcription factor is sufficient to confer the CRPC phenotype. Here, we show that loss of CDK12 promotes MYC activity, which renders the cells dependent on the otherwise non‐essential splicing regulatory kinase SRSF protein kinase 1 (SRPK1). High MYC expression is associated with increased levels of SRPK1 in patient samples, and overexpression of MYC sensitizes prostate cancer cells to SRPK1 inhibition using pharmacological and genetic strategies. We show that Endovion (SCO‐101), a compound currently in clinical trials against pancreatic cancer, phenocopies the effects of the well‐characterized SRPK1 inhibitor SRPIN340 on nascent transcription. This is the first study to show that Endovion is an SRPK1 inhibitor. Inhibition of SRPK1 with either of the compounds promotes transcription elongation, and transcriptionally activates the unfolded protein response. In brief, here we discover that CDK12 inactivation promotes MYC signaling in an SRPK1‐dependent manner, and show that the clinical grade compound Endovion selectively targets the cells with CDK12 inactivation.

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Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects

Cited by 97 publications

References 319 publications

Splicing accuracy varies across human introns, tissues and age

Splicing accuracy varies across human introns, tissues and age

Improved detection of aberrant splicing using the Intron Jaccard Index

CDK12‐inactivation‐induced MYC signaling causes dependency on the splicing kinase SRPK1

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