SRSF3 promotes pluripotency through Nanog mRNA export and coordination of the pluripotency gene expression program
- Monash University, Australia
- The Francis Crick Institute, United Kingdom
Abstract
The establishment and maintenance of pluripotency depend on precise coordination of gene expression. We establish serine-arginine rich splicing factor 3 (SRSF3) as an essential regulator of RNAs encoding key components of the mouse pluripotency circuitry, SRSF3 ablation resulting in the loss of pluripotency and its overexpression enhancing reprogramming. Strikingly, SRSF3 binds to the core pluripotency transcription factor Nanog mRNA to facilitate its nucleo-cytoplasmic export independent of splicing. In the absence of SRSF3 binding, Nanog mRNA is sequestered in the nucleus and protein levels are severely downregulated. Moreover, SRSF3 controls the alternative splicing of the export factor Nxf1 and RNA regulators with established roles in pluripotency, and the steady-state levels of mRNAs encoding chromatin modifiers. Our investigation links molecular events to cellular functions by demonstrating how SRSF3 regulates the pluripotency genes and uncovers SRSF3-RNA interactions as a critical means to coordinate gene expression during reprogramming, stem cell self-renewal and early development.
Data availability
Sequencing data sets have been deposited in GEO under accession codes GSE101905 and GSE113794. The iCLIP data has been made available in the public version of iCount (http://icount.biolab.si; search for SRSF3).
Article and author information
Author details
Madara Ratnadiwakara
Igor Ruiz de los Mozos
Funding
National Health and Medical Research Council (GNT1043092)
- Traude H Beilharz
- Anja S Knaupp
- Minna-Liisa Anko
Australian Research Council
- Jose M Polo
Aatos and Jane Erkko Foundation
- Minna-Liisa Anko
Sylvia and Charles Viertel Charitable Foundation
- Jose M Polo
National Health and Medical Research Council (GNT1042851)
- Traude H Beilharz
- Anja S Knaupp
- Minna-Liisa Anko
National Health and Medical Research Council (GNT1092280)
- Traude H Beilharz
- Anja S Knaupp
- Minna-Liisa Anko
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Juan Valcárcel, Centre de Regulació Genòmica (CRG), Barcelona, Spain
Ethics
Animal experimentation: All animal work was performed in strict accordance with the Australian code for thecare and use of animals for scientific purposes (NHMRC) and the protocols were approved by the Monash University Animal Ethics Committee(MARP-2014-004).
Version history
- Received: April 10, 2018
- Accepted: May 5, 2018
- Accepted Manuscript published: May 9, 2018 (version 1)
- Version of Record published: May 22, 2018 (version 2)
Copyright
© 2018, Ratnadiwakara et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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SRSF3 promotes pluripotency through Nanog mRNA export and coordination of the pluripotency gene expression program
eLife 7:e37419.
https://doi.org/10.7554/eLife.37419
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