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Title: An investigation of the highly conserved long non-coding RNA CEROX1
Author: Roberts, Kenny
ISNI:       0000 0004 8507 3056
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Amid growing catalogues of long non-coding RNAs (lncRNAs), experimentally characterised examples are few, especially for the recently identified subpopulation that are enriched in the cytoplasm. Amongst these are lncRNAs whose activity is proposed to be mediated by the competitive endogenous RNA (ceRNA) mechanism. De-repression of miRNA targets results in concerted gene expression changes following ceRNA modulation in numerous in vitro models, but evidence of in vivo physiological relevance is lacking. In light of this, the novel human lncRNA CEROX1 was subjected to a multifaceted characterisation to investigate its potential as a physiologically important candidate ceRNA. In vitro molecular biology and in silico bioinformatic approaches were used to investigate the expression, conservation, activity, and regulation of CEROX1. It was found that CEROX1 is both extremely highly expressed and highly conserved, being expressed and enriched in the central nervous system of eutherian mammals. In particular, CEROX1 is highly enriched in cells of the oligodendrocyte lineage, and putatively associated with the process of oligodendrocyte differentiation. Modulation of CEROX1 and its murine orthologue Cerox1 in vitro results in concerted regulation of complex I of the mitochondrial electron transport chain; these are therefore the first lncRNAs identified with such a role. In line with its putative activity in regulating energy metabolism in the developing CNS, CEROX1 was found to be upregulated in vitro in response to calcium signalling, which contributes substantially to cell signalling pathways between neurons and glia including oligodendrocytes. In addition to the conserved mitochondria-regulating role of CEROX1, evidence of translation of a 234 residue open reading frame was uncovered in vitro and in vivo, suggesting recent evolution of the locus towards a protogene state. This work highly supports CEROX1 as a promising in vivo ceRNA candidate, although future study is required to pursue its role in regulating energy metabolism in the CNS.
Supervisor: Davies, Kay E. ; Ponting, Chris P. ; Sirey, Tamara M. ; Oliver, Peter L. Sponsor: University of Oxford ; Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available