Stem cells as a research model for trinucleotide repeat instability
PhD students: Lise Barbe, Silvie Franck
Lab technician: Pierre Hilven
Both hESC and iPSC have been proposed as tools for in vitro disease modelling, and the interest in this topic is intense, see for instance here. They could be used for the identification of disease biomarkers and to test the efficacy of new drugs or other types of therapies. This is particularly relevant for those diseases where animal models have been disappointing, or even not available. Moreover, if we would be able to replace animal models by in vitro hESC and iPSC models, this would mean a significant reduction in the number of lab animals used in medical research. One type of diseases for which disease modelling in hPSC has often been proposed are a group of neurodegenerative disorders that are caused by so-called dynamic mutations.
These diseases such as Huntington's disease, myotonic dystrophy type 1 and fragile X syndrome are caused by the instability displayed by long trinucleotide repeats. For these diseases, there is currently no effective treatment to prevent or delay the progression of the disease.
All these disorders share common characteristics such as the relationship between age of onset and the number of repeats in the tract, or the genetic anticipation upon transmission to the next generation. However, there are also striking differences. The degree of instability of the trinucleotide repeat does not only depend on its size, but also on its sequence and on the tissue studied.
Intergenerational instability occurs during gametogenesis when the trinucleotide repeat is over a certain threshold size and can change (often increasing in size), leading to the phenomenon of genetic anticipation (i.e. the aggravation of the symptoms and earlier age of onset from one generation to the next). In somatic tissues, the Huntington's repeat is stable, except for the brain. In contrast, the repeat causing myotonic dystrophy type I presents a broad somatic instability. Given the complexity of the findings, it is not surprising that the mechanisms of trinucleotide repeat instability are still a subject of intense investigation.
The aims of this project are:
- To characterise the behaviour of the trinucleotide repeats in the hESC lines derived from preimplantation embryos shown to be affected after preimplantation genetic diagnosis, and iPSC lines derived from patients who donated a skin biopsy
- To dissect the different aspects of trinucleotide instability making use of hESC and iPSC. Such aspects are for instance DNA methylation of the neighbouring DNA and the influence of DNA repair proteins that are known to erroneously repair the trinucleotide track
- These aspects are studied both in undifferentiated hESC and iPSC and differentiated derivatives. Therefore, we differentiate our hESC and iPSC into disease-relevant cells such as cardiomyocytes, retinal cells and osteogenic progenitor cells
Our work is sponsored by the major Flemish granting agencies FWO and IWT. We have also received continuous support from the Association Belge contre les Maladies neuro-Musculaires. We are also deeply indebted to Mrs Mireille Aerens, holder of the Mireille Aerens Chair at the Vrije Universiteit Brussel who generously sponsored the PhD of Lise Barbe.
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