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Investigating how alternative splicing processes affect cartilage biology from development to old age


Biosciences Institute

Dr L Reynard , Dr S Tew , Prof D Elliott Friday, January 22, 2021 Competition Funded PhD Project (Students Worldwide)
Newcastle United Kingdom Bioinformatics Cell Biology Molecular Biology

About the Project

Healthy cartilage in our joints is essential for us to maintain an active life into old age, with cartilage breakdown causing chronic pain, joint stiffness and reduced mobility. Chondrocytes, the only cell type present in cartilage, have a specialised phenotype that is initiated during development and then maintained throughout life. Successful maintenance of this chondrocyte phenotype is important for healthy joint ageing, whilst improved understanding of cartilage differentiation from stem cells is important for improving cartilage tissue regeneration approaches. 

Alternative RNA splicing (AS) and alternative polyadenylation (AP) are two essential mechanisms for the post-transcriptional control of gene expression in eukaryotes. Over 95% of multi-exonic genes are alternatively spliced in humans, allowing a single gene to encode multiple protein isoforms with different (sometimes antagonistic) functions, distinct subcellular localisations and diverse protein-protein interactions. Alternative polyadenylation results in transcripts pools that share similar protein coding regions but have different length 3’UTRs with different transcript stabilities. These two regulatory mechanisms are crucial for normal physiological processes including tissue development, differentiation and homeostasis. Post-transcriptional gene regulation is dysregulated during ageing, with abnormal AS and AP linked to several age-related pathologies including cancer and cardiovascular disease.

The role of AS and AP in cartilage development, health, age-related dysfunction and disease has not yet been explored at the genome wide level. This studentship offers an exciting opportunity to investigate the role of alternative mRNA isoforms in human cartilage function across the lifespan, from embryonic development to old age. The project will combine bioinformatics analysis with molecular biology techniques including qRT-PCR, western blot, human cell culture and biochemical assays. Cutting-edge CRISPR-Cas9 genetic editing approaches and antisense oligonucleotides will also be used to examine the function of specific age-related mRNAs in cartilage homeostasis.

The student will be primarily supervised by Dr Louise Reynard at Newcastle University, a world-leader in genetic and epigenetic regulation of cartilage gene expression. They will be co-supervised by Dr Simon Tew at the University of Liverpool, a pioneer in understanding post-transcriptional gene regulation in cartilage, and Prof David Elliott at Newcastle University, an expert in alternative splicing. In addition, the project involves placement periods with Dr Tew in Liverpool. The data generated by this studentship will reveal insight into the biological processes underlying cartilage ageing, provide new avenues for improving cartilage regenerative medicine approaches and identify potential targets for therapeutic intervention to treat cartilage age-related dysregulation.

Informal enquiries may be made to

HOW TO APPLY 

Applications should be made by emailing with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.

In addition to the CV and covering letter, please email a completed copy of the Newcastle-Liverpool-Durham (NLD) BBSRC DTP Studentship Application Details Form (Word document) to , noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

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2. Histone ChIP-Seq identifies differential enhancer usage during chondrogenesis as critical for defining cell-type specificity. FASEB J. 2020 34(4):5317-5331. doi: 10.1096/fj.201902061RR.
3. Identification of a novel, methylation-dependent, RUNX2 regulatory region associated with osteoarthritis risk. Hum Mol Genet. 2018 1;27(19):3464-3474. doi: 10.1093/hmg/ddy257.
4. Translational regulation contributes to the secretory response of chondrocytic cells following exposure to Interleukin-1ß. J Biol Chem. 2019 294(35), 13027-13029. DOI: 10.1074/jbc.RA118.006865.
5. RNA binding proteins regulate anabolic and catabolic gene expression in chondrocytes. Osteoarthritis Cartilage. 2016 24(7):1263-73. DOI: 10.1016/j.joca.2016.01.988.
6. Transcriptome-wide analysis of messenger RNA decay in normal and osteoarthritic human articular chondrocytes. Arthritis Rheumatol. 2014 66(11):3052-61. DOI: 10.1002/art.38849.
7. Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. Elife. 2019 8. pii: e47678. DOI: 10.7554/eLife.47678.
8. An ancient germ cell-specific RNA-binding protein protects the germline from cryptic splice site poisoning. Elife. 2019 8.pii: e39304. DOI: 10.7554/eLife.39304.
9. SUPPA2: fast, accurate, and uncertainty-aware differential splicing analysis across multiple conditions. Genome Biol 2018 19(1):40. DOI: 10.1186/s13059-018-1417-1.
10. Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons. Nat Commun. 2014;5:4760. DOI: 10.1038/ncomms5760.
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