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Genetically regulated human NODAL splice variants are differentially post-transcriptionally processed and functionally distinct

Scott D Findlay, Olena Bilyk, Kiefer Lypka, Andrew J Waskiewicz, Lynne-Marie Postovit

Preprint posted on 4 March 2018 https://www.biorxiv.org/content/early/2018/03/04/276170

Newly discovered human-specific NODAL variant expression downregulates LIFR in human stem cells

Selected by Pierre Osteil

Categories: developmental biology

Background:

NODAL is a growth factor of the TGF-β signalling superfamily that plays critical roles during embryogenesis (particularly in the establishment of left-right asymmetry) and in the maintenance of cancer cells. NODAL has been studied extensively in vertebrate development and in stem cells (1) but this is the first study showing a human-specific splice variant. This article is a follow up study of a previous preprint by the same group (2) relating the discovery of several NODAL splice variants (including an antisense and a circular transcripts) indicating that a lot remains to discover about how NODAL is regulated and affects its targets. Here the authors elucidate a possible function of one of the splice variants that could be involved in the discrepancies observed between naïve and primed embryonic stem cells.

 

The data

In this study, the authors describe one splice variant resulting from a human specific Single Nucleotide Polymorphism (SNP) in the second intron of NODAL (rs2231947 C/T). This intron leads to a transcript that contains a supplementary exon and a Premature Termination Codon, resulting in the translation of a distinct protein. Using morpholinos, they were able to inhibit specifically this variant in human embryonic stem cells (hESC), which led to an increase of Leukemia Inhibitory Factor Receptor (LIFR). Its expression is generally shut down in hESC conversely to mouse species. Both constitutive and human-specific transcripts were injected into zebrafish embryos to assess canonical NODAL signalling activity. While the constitutive NODAL injection leads to a disruption of gastrulation, the variant did not, suggesting different action mechanisms. Moreover, the alternative splicing of NODAL leads to partial disruption of the TGB-β superfamily domain that may impact on NODAL signalling.

Finally, the authors found that the two proteins are differently N-glycosylated, resulting in an increased level of excretion of the variant protein compared to the constitutive NODAL. Differential secretion may thus partially explain their different functions.

Image reproduced from Findlay et al., 2018 Fig 3A and 3B

 

Why did I choose this article?

The newly described NODAL variant could be responsible for the loss of LIFR observed in primed ESCs of non-murine species. The SNP is specific to the human genome and might explain why human stem cells cannot be stabilised at the naïve state of pluripotency. My PhD project was articulated around the understanding of naïve versus primed pluripotency, and I highlighted this article for the clues it gives toward deciphering pluripotency regulatory mechanisms.

 

Open questions

  • Have you checked hESC pluripotency status when the NODAL variant is knocked down? Could you observe upregulation of genes associated to naïve pluripotency?
  • Is this variant present in other mammals such as rabbit or monkey? If yes, you might be able to link the presence of this variant to the impossibility of establishing naïve pluripotency in non-murine mammals?

 

Related research

  1. Pauklin S, Vallier L (2015) Activin/Nodal signalling in stem cells. Development 142(4):607–619.
  2. Findlay SD, Postovit L-M (2018) Comprehensive characterization of transcript diversity at the human NODAL locus. bioRxiv:1–26.

 

Tags: hesc, naive, nodal, primed, stem cell

Posted on: 3 April 2018

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