MicroRNAs (miRNAs) are short non-coding RNAs ~22 nt in length that function as important regulators of gene expression1. MiRNAs have been found to be involved in virtually every cellular process and are essential in development, differentiation and homeostasis. Dysregulation of miRNA levels is a hallmark of many human diseases including cancer2, neurodegenerative diseases, metabolic diseases and cardiovascular diseases. Importantly, miRNAs are emerging as promising targets for precision medicine that will enable more accurate diagnosis and provide new therapeutics, tailored for specific diseases and individual patients.
miRNA genes are transcribed in the nucleus by RNA polymerase II, with the long primary transcript, termed pri-miRNA, harboring a hairpin structure, which comprises the miRNA sequence. Pri-miRNA molecules undergo nuclear and cytoplasmic processing events, carried out by the endoribonucleases, DROSHA and DICER, respectively, to produce mature miRNAs that are loaded onto the RISC (RNA-induced silencing complex) to exert their biological function.
miRNAs biogenesis is regulated post-transcriptionally by RNA-binding proteins that bind to the miRNA precursors3 but very little is known about the regulation of miRNA biogenesis at a global scale in cancer patients. Recently, we have identified a new RNA-binding protein Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Beta (HADHB) that controls the production of miRNA-3294. HADHB is a protein that catalyzes the last steps of beta-oxidation of long chain fatty acids and its high levels are associated with favorable survival rates in renal cancer. Many studies have shown that aberrant miRNAs levels or fatty acids metabolism correlate with malignant phenotypes, including cancerogenesis. However, the precise mechanism explaining how HADHB regulates miRNA biogenesis and fatty acid metabolism in cancer remains unknown. By using integrative approaches in transcriptomics and molecular biology, this project aims to expand our knowledge about the regulation of miRNA production and cellular metabolism, which are essential to understand and treat human diseases that arise from deregulated gene expression.
This PhD project aims to decipher the mechanisms of miRNA deregulation in cancer.
Our specific questions are:
1. Which cellular processes contribute to deregulation of miRNA levels in cancer patients?
2. Which proteins regulate the production of miRNAs in cancer cells?
3. What is the role of HADHB in cancer and in global regulation of miRNA biogenesis?
During this project, the PhD student will undergo comprehensive training in population health, computational biology, bioinformatics and genomics by analyzing large datasets of RNAseq and small RNAseq samples from cancer patients obtained through TCGA and Scottish and Swedish sources and investigating HADHB knock out and overexpression phenotypes on the transcriptome and proteome levels. The student will thereby contribute to our understanding of gene regulation in cancer. Under supervision, the student gains a deep understanding of research in cancer and miRNA biology and conducts cutting-edge molecular and genomic approaches. Using interdisciplinary approaches will equip the student with paramount knowledge and a competitive skillset.
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.
All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow. http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919
Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.
For more information about Precision Medicine visit: http://www.ed.ac.uk/usher/precision-medicine
1. Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11, 597-610 (2010).
2. Lin, S. & Gregory, R.I. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 15, 321-33 (2015).
3. Michlewski, G. & Caceres, J.F. Post-transcriptional control of miRNA biogenesis. Rna 25, 1-16 (2019).
4. Downie Ruiz Velasco, A. et al. Posttranscriptional Regulation of 14q32 MicroRNAs by the CIRBP and HADHB during Vascular Regeneration after Ischemia. Mol Ther Nucleic Acids 14, 329-338 (2018).