Article: article from journal or magazin.
Early transcriptional changes linked to naturally occurring Huntington's disease mutations in neural derivatives of human embryonic stem cells.
Human Molecular Genetics
Publication types: Journal ArticlePublication Status: ppublish. Authors contributions: M.F.: hESCs culture and directed neural differentiation, NSC transgenesis,RNA samples collection and analyses, data collection and analysis; F.B.-R.: hESCs neuronal differentiation, RNA and protein samples collection and analyses; A.R.: RNA analysis, generation of Illumina array data and QRT-PCR validation; N.L.: hESCs culture, RNA samples collection and analyses; P.G.: microarray data analyses and bioinformatics. S.A., C.B.: RNA and protein sample collection and analyses; A.B.: hESC and NSC culture; N.D.: HTT knock-down and overexpression lentiviruses; L.J.: Illumina study design, bioinformatics and in silico meta analyses, editing of manuscript; M.P.: conception, study design, participation to writing; N.D.A.: study design, data analysis, interpretation and writing of manuscript; A.P.: study design, NSC transgenesis, molecular assays, data analysis, interpretation and writing of manuscript.
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.
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