SRSF3 maintains transcriptome integrity in oocytes by regulation of alternative splicing and transposable elements

Dang Vinh Do; Bernhard Strauss; Engin Cukuroglu; Iain Macaulay; Keng Boon Wee; Tim Xiaoming Hu; Ruiz De Los Mozos Igor; Caroline Lee; Andrew Harrison; Richard Butler; Sabine Dietmann; Ule Jernej; John Marioni; Christopher W J Smith; Jonathan Göke; M Azim Surani

doi:10.1038/s41421-018-0032-3

SRSF3 maintains transcriptome integrity in oocytes by regulation of alternative splicing and transposable elements

Cell Discov. 2018 Jun 19:4:33. doi: 10.1038/s41421-018-0032-3. eCollection 2018.

Authors

Dang Vinh Do^{1

2}, Bernhard Strauss¹, Engin Cukuroglu³, Iain Macaulay⁴, Keng Boon Wee^{5

6}, Tim Xiaoming Hu⁷, Ruiz De Los Mozos Igor⁸, Caroline Lee^{1

2}, Andrew Harrison¹, Richard Butler¹, Sabine Dietmann⁹, Ule Jernej⁸, John Marioni^{8

10

11}, Christopher W J Smith¹², Jonathan Göke³, M Azim Surani^{1

2}

Affiliations

¹ 1Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN UK.
² 2Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3DY UK.
³ 3Computational and Systems Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore, 138672 Singapore.
⁴ 4Earlham Institute, Norwich Research Park, Norwich, NR4 7UH UK.
⁵ 5Department Fluid Dynamics, Institute of High Performance Computing, 1 Fusionopolis Way, Singapore, 138632 Singapore.
⁶ 6Biomolecular Function Discovery Division, Bioinformatics Institute, 30 Biopolis Street, Singapore, 138671 Singapore.
⁷ EMBL European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SD, Cambridge, UK.
⁸ 8Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
⁹ 9Wellcome Trust Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK.
¹⁰ 10Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE UK.
¹¹ Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.
¹² 12Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW UK.

Abstract

The RNA-binding protein SRSF3 (also known as SRp20) has critical roles in the regulation of pre-mRNA splicing. Zygotic knockout of Srsf3 results in embryo arrest at the blastocyst stage. However, SRSF3 is also present in oocytes, suggesting that it might be critical as a maternally inherited factor. Here we identify SRSF3 as an essential regulator of alternative splicing and of transposable elements to maintain transcriptome integrity in mouse oocyte. Using 3D time-lapse confocal live imaging, we show that conditional deletion of Srsf3 in fully grown germinal vesicle oocytes substantially compromises the capacity of germinal vesicle breakdown (GVBD), and consequently entry into meiosis. By combining single cell RNA-seq, and oocyte micromanipulation with steric blocking antisense oligonucleotides and RNAse-H inducing gapmers, we found that the GVBD defect in mutant oocytes is due to both aberrant alternative splicing and derepression of B2 SINE transposable elements. Together, our study highlights how control of transcriptional identity of the maternal transcriptome by the RNA-binding protein SRSF3 is essential to the development of fertilized-competent oocytes.

Abstract

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