TY  - INPR
A1  - Linker, Stephanie M.
A1  - Urban, Lara
A1  - Clark, Stephen
A1  - Chhatriwala, Mariya
A1  - Amatya, Shradha
A1  - McCarthy, Davis J.
A1  - Ebersberger, Ingo
A1  - Vallier, Ludovic
A1  - Reik, Wolf
A1  - Stegle, Oliver
A1  - Bonder, Marc Jan
T1  - Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity
T2  - bioRxiv
N2  - 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.
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/85850
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-858507
UR  - https://www.biorxiv.org/content/10.1101/328138v1
IS  - 32813 Version 1
PB  - bioRxiv
ER  -