SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export

Müller-McNicoll, Michaela; Botti, Valentina; Domingues, António Miguel de Jesus; Brandl, Holger; Schwich, Oliver D.; Steiner, Michaela C.; Curk, Tomaž; Poser, Ina; Zarnack, Kathi; Neugebauer, Karla M.

doi:10.1101/gad.276477.115

Cited by 258 publications

(357 citation statements)

References 67 publications

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“…To confirm this, we calculated the average number of bases different (edit distance) between UMIs at a given genomic locus and compared the distribution of average edit distances to a null distribution generated by randomly sampling (Methods). Using iCLIP data (Müller-McNicoll et al 2016), we confirmed that the UMIs are more similar to one another than expected according to the null, strongly suggesting sequencing and/ or PCR errors are generating artifactual UMIs (Methods; Fig. 1B; for other data sets, see Supplemental Fig.…”

Section: Resultssupporting

confidence: 58%

“…We next sought to examine the effect of these methods on real data, starting with the previously mentioned iCLIP data, which includes 3-6 replicates for nine proteins (Müller-McNicoll et al 2016). For replicate 1, the distribution of the average edit distance between UMIs present at each genomic locus showed enrichment for single-edit distance relative to a null distribution from random sampling, taking into account the genome-wide distribution of UMIs (Fig.…”

Section: Comparing Methods With Iclip Datamentioning

confidence: 99%

“…In order to measure reproducibility of their data, Müller-McNicoll et al (2016) measured the Spearman's rank correlation between the numbers of significant tags in each exon across the genome. We repeated this calculation with data processed, using either the unique or directional method, and compared the average Spearman's correlation between each sample and other replicates of the same pull down.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

“…iCLIP Raw sequence was obtained from the European Nucleotide Archive (accessions SRP059277 and ERR039854) (Tollervey et al 2011;Müller-McNicoll et al 2016). Raw sequences were processed to move the UMI sequences to the read name using "umi_tools extract".…”

Section: Real Datamentioning

confidence: 99%

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UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy

2017

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Unique Molecular Identifiers (UMIs) are random oligonucleotide barcodes that are increasingly used in high-throughput sequencing experiments. Through a UMI, identical copies arising from distinct molecules can be distinguished from those arising through PCR amplification of the same molecule. However, bioinformatic methods to leverage the information from UMIs have yet to be formalized. In particular, sequencing errors in the UMI sequence are often ignored or else resolved in an ad hoc manner. We show that errors in the UMI sequence are common and introduce network-based methods to account for these errors when identifying PCR duplicates. Using these methods, we demonstrate improved quantification accuracy both under simulated conditions and real iCLIP and single-cell RNA-seq data sets. Reproducibility between iCLIP replicates and single-cell RNA-seq clustering are both improved using our proposed network-based method, demonstrating the value of properly accounting for errors in UMIs. These methods are implemented in the open source UMI-tools software package.

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Section: Resultssupporting

confidence: 58%

Section: Comparing Methods With Iclip Datamentioning

confidence: 99%

Section: Wwwgenomeorgmentioning

confidence: 99%

Section: Real Datamentioning

confidence: 99%

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UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy

2017

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“…However, the depletion of each of the SRSF1-7 proteins in murine cells only affect the nuclear export of 0.5-2% of mRNAs despite interactions with thousands of transcripts [43] . Taken together, the NXF1-dependent nuclear export adaptor function appears to involve redundancy and/or cooperation in cultured and differentiated cells.…”

Section: The Nuclear Export Of Bulk Mrnasmentioning

confidence: 99%

SRSF1-dependent nuclear export of C9ORF72 repeat transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection

Castelli

Lin

Ferraiuolo

et al. 2018

Ther Targets Neurol Dis

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Microsatellite repeat expansions cause several incurable and lethal neurodegenerative disorders including ataxias, myotonic dystrophy, Huntington's disease and C9ORF72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Abnormal repeat transcripts generated from the expanded loci are substrates of repeat-associated non-AUG (RAN) translation, an unconventional form of translation leading to the production of polymeric repeat proteins with cytotoxic and aggregating properties. The mechanisms involved in the pathogenesis of microsatellite repeat expansion disorders remain a hotly debated topic. They are shared between toxic loss/gain of functions due to intranuclear RNA foci that sequesters RNA-binding proteins and RAN translation of repeat proteins in the cytoplasm. We recently elucidated the molecular mechanism driving the nuclear export of C9ORF72 repeat transcripts and showed for the first time that this pathway can be manipulated to confer neuroprotection. Strikingly, we discovered that intron-retaining C9ORF72 repeat transcripts hijack the physiological NXF1-dependent export pathway by selective RNA-repeat sequestration of SRSF1. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the survival of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in Drosophila (Hautbergue et al. Nature Communications 2017; 8:16063). In this invited Research Highlight review, we aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a summary of the published research and highlight the significance of these findings as a novel therapeutic strategy for neuroprotection in C9ORF72-ALS/FTD. In addition, we emphasize that protein sequestration, often thought as of inducing loss-of-function mechanisms, can also trigger unwanted protein interactions and toxic gain-of-functions.Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Neurodegeneration; Microsatellite repeat expansions; C9ORF72; RNA nuclear export; SRSF1; NXF1; RAN translation; Therapeutic strategy To cite this article: Lydia M. Castelli, et al. SRSF1-dependent nuclear export of C9ORF72 repeat-transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection. Ther Targets Neurol

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Regulation of alternative mRNA splicing: old players and new perspectives

Dvinge

2018

FEBS Letters

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Nearly all human multiexon genes are subject to alternative splicing in one or more cell types. The splicing machinery therefore has to select between multiple splice sites in a context-dependent manner, relying on sequence features in cis- and trans-acting splicing regulators that either promote or repress splice site recognition and spliceosome assembly. However, the functional coupling between multiple gene regulatory layers signifies that splicing can also be modulated by transcriptional or epigenetic characteristics. Other, less obvious, aspects of alternative splicing have come to light in recent years, often involving core components of the spliceosome previously thought to perform a basal rather than a regulatory role in splicing. Together this paints a highly dynamic picture of splicing regulation, where the final splice site choice is governed by the entire transcriptional environment of a gene and its cellular context.

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SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export

Cited by 258 publications

References 67 publications

UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy

UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy

SRSF1-dependent nuclear export of C9ORF72 repeat transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection

Regulation of alternative mRNA splicing: old players and new perspectives

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