Early transcriptional changes linked to naturally occurring Huntington's disease mutations in neural derivatives of human embryonic stem cells
| Autor: | Lesley Jones, Sophie Aubert, Nicole Déglon, Aurore Bugi, Peter Giles, Marta Ruiz, Fany Bourgois-Rocha, Anselme L. Perrier, Nathalie Lefort, Nicholas D. Allen, Marc Peschanski, Amanda Redfern, Caroline Bonnefond, Maxime Feyeux |
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| Rok vydání: | 2012 |
| Předmět: |
Huntingtin
Transcription Genetic Mutant Nerve Tissue Proteins Biology medicine.disease_cause Models Biological Cell Line Huntington's disease Neural Stem Cells Genetics medicine Huntingtin Protein Humans Molecular Biology Genetics (clinical) Embryonic Stem Cells Regulation of gene expression Neurons Mutation Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Reproducibility of Results General Medicine medicine.disease Neural stem cell Gene expression profiling Huntington Disease Gene Expression Regulation Transcriptome |
| Zdroj: | Human molecular genetics. 21(17) |
| ISSN: | 1460-2083 |
| Popis: | Huntington's disease (HD) is characterized by a late clinical onset despite ubiquitous expression of the mutant gene at all developmental stages. How mutant huntingtin impacts on signalling pathways in the pre-symptomatic period has remained essentially unexplored in humans due to a lack of appropriate models. Using multiple human embryonic stem cell lines derived from blastocysts diagnosed as carrying the mutant huntingtin gene by pre-implantation genetic diagnosis, we explored early developmental changes in gene expression using differential transcriptomics, combined with gain and loss of function strategies. We demonstrated a down-regulation of the HTT gene itself in HD neural cells and identified three genes, the expression of which differs significantly in HD cells when compared with wild-type controls, namely CHCHD2, TRIM4 and PKIB. Similar dysregulation had been observed previously for CHCDH2 and TRIM4 in blood cells from patients. CHCHD2 is involved in mitochondrial function and PKIB in protein kinase A-dependent pathway regulation, which suggests that these functions may be precociously impacted in HD. |
| Databáze: | OpenAIRE |
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