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dc.contributor.advisorMichlewski, Gracjanen
dc.contributor.advisorTollervey, Daviden
dc.contributor.authorNowak, Jakub Stanislawen
dc.date.accessioned2017-02-20T11:51:20Z
dc.date.available2017-02-20T11:51:20Z
dc.date.issued2016-06-28
dc.identifier.urihttp://hdl.handle.net/1842/20393
dc.description.abstractMany cellular functions depend on the tightly regulated expression of various proteins. Canonical control of the protein expression is associated with transcriptional regulation. However, the small non-coding RNAs called microRNAs (miRNAs) were identified as post-transcriptional regulators of gene expression. In a typical manner, miRNAs originate similarly to the coding RNAs and are processed in a multi-step maturation process. It has been shown that miRNAs are very important for the proper functioning of tissues. Interestingly, the human nervous system contains over 70% of all miRNAs; thus, the maturation process has to be tightly regulated. However, despite the important role of miRNAs, little is known about the mechanisms regulating their biogenesis. In my PhD project, I showed that during early stages of neuronal differentiation, Lin28a controls levels of neuro-specific miRNA-9. I demonstrated that Lin28a binds to the conserved terminal loop (CTL) of pre-miRNA-9 and decreases the cellular levels of miRNA-9 during retinoic acid-mediated neuronal differentiation of mouse teratocarcinoma P19 cells. I revealed that the Lin28a-mediated inhibition of miRNA-9 production was uridylation-independent. Furthermore, constitutive expression of GFP-tagged Lin28a reduced the levels of let-7a but not miRNA-9, whereas untagged Lin28a inhibited both miR-9 and let-7a during the course of neuronal differentiation. Using small RNAseq analysis of P19 cells with constitutive expression of Lin28a I showed that it controls many more miRNAs than previously recognised. Intriguingly, many miRNAs were upregulated by Lin28a overexpression. I demonstrated with high-throughput, the limited function of GFP-tagged Lin28a results, and I also showed that untagged Lin28a inhibits the production of a number of brain-specific miRNAs including miRNA-9. Finally, I revealed that 3’-5’exoribonuclease Dis3l2 was responsible for uridylation-independent degradation of pre-miRNA-9. Altogether, my results provided evidence that Lin28a has both positive and negative roles in the regulation of miRNA production and has a dual role in triggering pre-miRNA degradation.en
dc.contributor.sponsorWellcome Trusten
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionChoudhury, N.R., Nowak, J.S., Zuo, J., Rappsilber, J., Spoel, S.H., and Michlewski, G. (2014). Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation. Cell reports 9, 1265-1272.en
dc.relation.hasversionNowak, J.S., Choudhury, N.R., de Lima Alves, F., Rappsilber, J., and Michlewski, G. (2014). Lin28a regulates neuronal differentiation and controls miR-9 production. Nat Commun 5, 3687.en
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/
dc.subjectmiRNAen
dc.subjectneuronal differentiationen
dc.subjectRNA processingen
dc.titleDual role of Lin28a in the regulation of miRNA biogenesis during neuronal differentiationen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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