Epigenetics of mesenchymal stem cell differentiation to musculoskeletal tissue
| Dates: | 9 May 2014 |
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| Times: | 14:00 - 15:00 |
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| What is it: | Seminar |
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| Organiser: | Faculty of Life Sciences |
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| Who is it for: | University staff |
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| Speaker: | David Young |
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This seminar is part of the Manchester Tissue Regeneration & Stem Cell Network seminar series. Abstract: Epigenetic mechanisms are important regulators of differentiation but also increasingly seen as important players in disease. My group focuses on the various epigenetic mechanisms (including non-coding RNAs and DNA methylation) involved in both mesenchymal stem cell (BM-MSC) differentiation to chondrocytes and in chondrocytes from osteoarthritic (OA) patients.
DNA methylation is the archetypal epigenetic modification. Using global methylation analysis we identified changes associated with OA and BM-MSC differentiation. These data point to control of enhancer elements being critical regulators.
In terms of non-coding RNAs, microRNAs are essential for mouse limb development (endochondral ossification), as exemplified using both Dicer and miR-140, a cartilage specific miR, -null mice. Moreover, miR-140-null mice also develop an osteoarthritis-like disease, typified by the loss of cartilage. Using cellular models of chondrogenesis, starting from human mesenchymal stem cells (hMSC), and clinical patient cartilage samples we have identified miRNAs (and lncRNAs) expressed by chondrocytes. In terms of miRNAs we have focussed upon miR140, miR455 and miR324-5p. Interestingly, miR324-5p controls hedgehog signalling in by humans and mice, however, the mechanism of action appears different in both species.
We have also identified the lncRNAs differentially expressed in osteoarthritis or during chondrogenesis for the first time using RNA-seq. We have focussed on several which surround the master chondrocyte transcription factor SOX9 locus and confirmed their expression to be chondrocyte specific. Depletion of select lncRNAs by RNAi disrupts hMSC chondrogenesis, concomitant with reduced cartilage gene expression and matrix component production, indicating an essential role in chondrocyte biology.
Our ongoing examination into the epigenetic mechanisms and function sheds light on chondrocyte gene regulation and provides a greater understanding of mechanisms that become disrupted during the development of osteoarthritis.
Speaker
David Young
Organisation: Newcastle University
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Lecture Theatre
Michael Smith Building
Manchester
