Systems analysis of miR-199a/b-5p and multiple miR-199a/b-5p targets during chondrogenesis

Patel, Krutik, Barter, Matt, Soul, Jamie, Clark, Peter, Proctor, Carole, Clark, Ian, Young, David and Shanley, Daryl P. (2024) Systems analysis of miR-199a/b-5p and multiple miR-199a/b-5p targets during chondrogenesis. eLife, 12. ISSN 2050-084X

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Abstract

Changes in chondrocyte gene expression can contribute to the development of osteoarthritis (OA), and so recognition of the regulative processes during chondrogenesis can lead to a better understanding of OA. microRNAs (miRNAs) are key regulators of gene expression in chondrocytes/OA, and we have used a combined experimental, bioinformatic, and systems biology approach to explore the multiple miRNA–mRNA interactions that regulate chondrogenesis. A longitudinal chondrogenesis bioinformatic analysis identified paralogues miR-199a-5p and miR-199b-5p as pro-chondrogenic regulators. Experimental work in human cells demonstrated alteration of miR199a-5p or miR-199b-5p expression led to significant inverse modulation of key chondrogenic genes and extracellular matrix production. miR-199a/b-5p targets FZD6, ITGA3 and CAV1 were identified by inhibition experiments and verified as direct targets by luciferase assay. The experimental work was used to generate and parameterise a multi-miRNA 14-day chondrogenesis kinetic model to be used as a repository for the experimental work and as a resource for further investigation of this system. This is the first multi-miRNA model of a chondrogenesis-based system, and highlights the complex relationships between regulatory miRNAs, and their target mRNAs

Item Type:	Article
Additional Information:	Data availability statement: All scripts will be found in the following GitHub repository: https://github.com/Krutik6/MIR199ab5p-Chondrogenesis-Modelling-Paper/ (copy archived at Patel, 2024). The enhanced kinetic model can be found in the following biomodels repository MODEL2305010001. RNAseq data generated in this project can be found in GSE274379. Funding information: Dunhill Medical Trust (R476/0516); Novo Nordisk Fonden (NNF17OC0027812); Medical Research Council (MRC) (MR/P020941/1; MR/R502182/1); Versus Arthritis (22043)
Faculty \ School:	Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine
Depositing User:	LivePure Connector
Date Deposited:	16 Oct 2024 09:30
Last Modified:	16 Oct 2024 09:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/97037
DOI:	10.7554/eLife.89701.4

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