1. Chromosomes and Gene Expression
  2. Stem Cells and Regenerative Medicine

SRSF3 promotes pluripotency through Nanog mRNA export and coordination of the pluripotency gene expression program

  1. Madara Ratnadiwakara
  2. Stuart K Archer
  3. Craig I Dent
  4. Igor Ruiz de los Mozos
  5. Traude H Beilharz
  6. Anja S Knaupp
  7. Christian M Nefzger
  8. Jose M Polo
  9. Minna-Liisa Anko  Is a corresponding author
  1. Monash University, Australia
  2. The Francis Crick Institute, United Kingdom
https://doi.org/10.7554/eLife.37419
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Cite this article
  1. Madara Ratnadiwakara
  2. Stuart K Archer
  3. Craig I Dent
  4. Igor Ruiz de los Mozos
  5. Traude H Beilharz
  6. Anja S Knaupp
  7. Christian M Nefzger
  8. Jose M Polo
  9. Minna-Liisa Anko
(2018)
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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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).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Madara Ratnadiwakara

    Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7252-1823

  2. Stuart K Archer

    Bioinformatics Platform, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.

  3. Craig I Dent

    School of Biological Sciences, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.

  4. Igor Ruiz de los Mozos

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4097-6422

  5. Traude H Beilharz

    Biomedicine Discovery Institute, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.

  6. Anja S Knaupp

    Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.

  7. Christian M Nefzger

    Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.

  8. Jose M Polo

    Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.

  9. Minna-Liisa Anko

    Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
    For correspondence
    minni.anko@monash.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0446-3566

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.

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).

Reviewing Editor

  1. Juan Valcárcel, Centre de Regulació Genòmica (CRG), Barcelona, Spain

Version history

  1. Received: April 10, 2018
  2. Accepted: May 5, 2018
  3. Accepted Manuscript published: May 9, 2018 (version 1)
  4. 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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  1. Madara Ratnadiwakara
  2. Stuart K Archer
  3. Craig I Dent
  4. Igor Ruiz de los Mozos
  5. Traude H Beilharz
  6. Anja S Knaupp
  7. Christian M Nefzger
  8. Jose M Polo
  9. Minna-Liisa Anko
(2018)
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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