ZFAS1: a long non-coding RNA with novel implications for ribosome function

Long non-coding RNAs (lncRNAs) are a class of pervasively transcribed non-coding transcripts, regulating gene expression at both the transcriptional and post transcriptional levels. Many lncRNAs exhibit altered expression in diseases processes. Breast cancers show deregulated expression of lncRNAs, several of which contribute to breast cancer progression. The lncRNA of interest in this study is ZFAS1 that is differentially expressed in mouse mammary gland development and breast cancer. The primary objective of this thesis was to understand how ZFAS1 may contribute to regulation of cellular processes using breast cancer as a model. We have found ZFAS1 expressed in high abundance in all breast epithelial and cancer cell lines examined. It is expressed at least as five different isoforms, which are not restricted to either cytoplasm or nucleus. Surprisingly, given that ZFAS1 is not protein-coding, it was found to be localised with polysomes. Treatment with ribosomal elongation inhibitors and strategies to induce growth arrest did not change the abundance of ZFAS1 transcripts, suggesting that it does not regulate protein elongation. Induction of cell growth by serum starvation followed by refeeding increased the abundance of ZFAS1 and of 45S rRNA, a marker of ribosomal biogenesis. ZFAS1 knockdown abolished 45S rRNA induction after stimulation of cell growth and decreased phosphorylation of RPS6, a key ribosomal protein important for relaying extracellular signals to promote ribosome activity and biogenesis. Ribosome biogenesis, including in human muscle samples derived from participants after resistance exercise, and in hypertrophic mouse models were then investigated. ZFAS1 expression was induced after exercise in human muscle cells. Its upregulation is concordant with that of 45S rRNA, suggesting it may function in ribosome biogenesis. In mouse hypertrophic models, ZFAS1 expression was correlated with increased muscle mass and total ribosome content. ZFAS1’s mechanism of action was further investigated by examining possible protein binding partners via RNA pulldown. These preliminary studies suggest that ZFAS1 may interact with proteins involved in ribosome structure, biogenesis and function. Our studies investigating the association of ZFAS1 with ribosomes and its possible functions could serve as a model for other ribosome associated lncRNAs.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Health Science

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2017

Author dc:creator

• Hansji, Herah

Advisors dc:contributor.advisor

• Askarian-Amiri, M
• Finlay, G
• Leung, E

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/36341

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/36341