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

View ORCID ProfileStephanie Linker, View ORCID ProfileLara Urban, View ORCID ProfileStephen Clark, Mariya Chhatriwala, Shradha Amatya, View ORCID ProfileDavis 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 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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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 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 mechanism in eukaryotic cells to increase the effective number of functionally distinct gene products. Using bulk RNA sequencing, splicing variation has been studied both across human tissues and in genetically diverse individuals. 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 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 splicing rates in single cells can be accurately predicted based on sequence composition and other genomic features. We also identified a moderate but significant contribution from DNA methylation to splicing variation across cells. By combining sequence information and DNA methylation, we derived an accurate model (AUC=0.85) for predicting different splicing modes of individual cassette exons. These explain 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 component of DNA methylation variation on splicing.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 22, 2018.
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Combined single cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity
Stephanie Linker, Lara Urban, Stephen Clark, Mariya Chhatriwala, Shradha Amatya, Davis 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 Linker, Lara Urban, Stephen Clark, Mariya Chhatriwala, Shradha Amatya, Davis 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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