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Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity

View ORCID ProfileStephanie M. Linker, View ORCID ProfileLara Urban, View ORCID ProfileStephen Clark, Mariya Chhatriwala, Shradha Amatya, View ORCID ProfileDavis J. McCarthy, View ORCID ProfileIngo Ebersberger, View ORCID ProfileLudovic Vallier, View ORCID ProfileWolf Reik, View ORCID ProfileOliver Stegle, View ORCID ProfileMarc Jan Bonder
doi: https://doi.org/10.1101/328138
Stephanie M. Linker
1European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK
2European Molecular Biology Laboratory, Genome Biology Heidelberg, Germany
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  • ORCID record for Stephanie M. Linker
Lara Urban
1European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK
2European Molecular Biology Laboratory, Genome Biology Heidelberg, Germany
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Stephen Clark
3Epigenetics Programme, The Babraham Institute, Cambridge, UK
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Mariya Chhatriwala
4Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
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Shradha Amatya
4Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
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Davis J. McCarthy
1European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK
2European Molecular Biology Laboratory, Genome Biology Heidelberg, Germany
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Ingo Ebersberger
5Applied Bioinformatics Group, Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Str. 13, 60438 Frankfurt am Main, Germany
6Senckenberg Biodiversity and Climate Research Centre (BiK-F), Frankfurt am Main, Germany
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Ludovic Vallier
4Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
7Wellcome Trust – MRC Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge CB2 0SZ, UK
8Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK
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Wolf Reik
3Epigenetics Programme, The Babraham Institute, Cambridge, UK
4Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
9Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
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Oliver Stegle
1European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK
2European Molecular Biology Laboratory, Genome Biology Heidelberg, Germany
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Marc Jan Bonder
1European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK
2European Molecular Biology Laboratory, Genome Biology Heidelberg, Germany
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Abstract

Background Alternative splicing is a key regulatory mechanism in eukaryotic cells and increases the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied across human tissues and in genetically diverse populations. This has identified disease-relevant splicing events, as well as associations between splicing and genomic variations, including sequence composition and conservation. However, variability in splicing between single cells from the same tissue or cell type and its determinants remain poorly understood.

Results We applied parallel DNA methylation and transcriptome sequencing to differentiating human induced pluripotent stem cells to characterize splicing variation (exon skipping) and its determinants. Our results shows that variation in single-cell splicing can be accurately predicted based on local sequence composition and genomic features. We observe moderate but consistent contributions from local DNA methylation profiles to splicing variation across cells. A combined model that is built based on sequence as well as DNA methylation information accurately predicts different splicing modes of individual cassette exons (AUC=0.85). These categories include the conventional inclusion and exclusion patterns, but also more subtle modes of cell-to-cell variation in splicing. Finally, we identified and characterized associations between DNA methylation and splicing changes during cell differentiation.

Conclusions Our study yields new insights into alternative splicing at the single-cell level and reveals a previously underappreciated link between DNA methylation variation and splicing.

  • List of abbreviations

    PSI
    splicing ratio
    iPS cell
    induced pluripotent stem cell
    ES cell
    Embryonic stem cell
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    Posted November 06, 2018.
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    Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity
    Stephanie M. Linker, Lara Urban, Stephen Clark, Mariya Chhatriwala, Shradha Amatya, Davis J. McCarthy, Ingo Ebersberger, Ludovic Vallier, Wolf Reik, Oliver Stegle, Marc Jan Bonder
    bioRxiv 328138; doi: https://doi.org/10.1101/328138
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    Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity
    Stephanie M. Linker, Lara Urban, Stephen Clark, Mariya Chhatriwala, Shradha Amatya, Davis J. McCarthy, Ingo Ebersberger, Ludovic Vallier, Wolf Reik, Oliver Stegle, Marc Jan Bonder
    bioRxiv 328138; doi: https://doi.org/10.1101/328138

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