Long noncoding RNA <em>ZFAS1</em> in ribosome regulation: a riddle wrapped in a mystery inside an enigma — ASN Events
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Long noncoding RNA ZFAS1 in ribosome regulation: a riddle wrapped in a mystery inside an enigma (#101)

Herah Hansji 1 2 , Euphemia Leung 1 2 , Bruce Baguley 1 , Graeme Finlay 1 2 , David Cameron-Smith 3 , Vandre Casagrande Figuiredo 3 , Marjan Askarian-Amiri 1 2
  1. Auckland Cancer Society Research Centre, University of Auckland, Grafton, Auckland, New Zealand
  2. Molecular Medicine and Pathology, University of Auckland, Grafton, Auckland, New Zealand
  3. The Liggins Institute, University of Auckland, Grafton, Auckland, New Zealand

Ribosomes, central to protein synthesis in all cells, are complex multicomponent assemblies involving hundreds of molecular components in their function and biogenesis [1]. Despite being discovered in the mid-1950s and the subject of intense interest, much surrounding the regulation of the ribosome and its biogenesis remains unknown.

In this study, we propose that the lncRNA ZFAS1 has a novel role in ribosome biogenesis. ZFAS1 was originally discovered by microarray analysis in mouse mammary gland development [2]. We have shown in both mouse and human that the ZFAS1 transcript is present in both cytoplasm and nucleus in an isoform-independent manner. Despite lacking coding potential, we have found that ZFAS1 is associated with polysomes in the cytoplasm. When ribosomes are dissociated, ZFAS1 remains associated with the small 40S subunit [3].

Analysis of mouse microarray data from our previous study of mouse mammary glands [2] identified five ribosomal proteins (rps3, rps21, rps24, rpl22, rpl28) with the same expression pattern as Zfas1. These ribosomal proteins have roles in ribosome production, assembly, and maturation. TCGA gene expression data confirmed similar expression for ZFAS1 and nominated ribosomal proteins in human normal and breast cancer samples.

Further studies in models of ribosome biogenesis found that expression of ZFAS1 is induced after exercise in human muscle cells [4]. Its upregulation is concordant with that of 45S rRNA, suggesting it may function in ribosome biogenesis. Mouse IGF overexpressing and myostatin knockdown-/- models exhibit larger muscle mass compared to WT controls. Increased muscle mass requires higher rates of protein synthesis and elevated  levels of ribosomes. ZFAS1 expression is correlated with this increased muscle mass as well as with total RNA concentrations, providing further evidence that ZFAS1 may be involved in ribosome regulation.

Currently we are investigating the role of ZFAS1 in pull down systems and using CRISPR/Cas9 to knock down ZFAS1 to explore its role in this complex process.

Reference:

  1. Thomson, E., et al., (2013) J Cell Sci. 126, 4815-21
  2. Askarian-Amiri, ME., et al., (2011) RNA 17: 878-91.
  3. Hansji, H., et al., (2016) RNA Biology (manuscript submitted).
  4. Figueiredo, VC., et al., (2016). Physiol Rep. 4(2). pii: e12670.
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