Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart

Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins School of Medicine, 1830 East Monument Street, Baltimore, MD 21205, USA.
Genome biology (Impact Factor: 10.81). 02/2005; 6(13):R107. DOI: 10.1186/gb-2005-6-13-r107
Source: PubMed


Down syndrome, caused by trisomic chromosome 21, is the leading genetic cause of mental retardation. Recent studies demonstrated that dosage-dependent increases in chromosome 21 gene expression occur in trisomy 21. However, it is unclear whether the entire transcriptome is disrupted, or whether there is a more restricted increase in the expression of those genes assigned to chromosome 21. Also, the statistical significance of differentially expressed genes in human Down syndrome tissues has not been reported.
We measured levels of transcripts in human fetal cerebellum and heart tissues using DNA microarrays and demonstrated a dosage-dependent increase in transcription across different tissue/cell types as a result of trisomy 21. Moreover, by having a larger sample size, combining the data from four different tissue and cell types, and using an ANOVA approach, we identified individual genes with significantly altered expression in trisomy 21, some of which showed this dysregulation in a tissue-specific manner. We validated our microarray data by over 5,600 quantitative real-time PCRs on 28 genes assigned to chromosome 21 and other chromosomes. Gene expression values from chromosome 21, but not from other chromosomes, accurately classified trisomy 21 from euploid samples. Our data also indicated functional groups that might be perturbed in trisomy 21.
In Down syndrome, there is a primary transcriptional effect of disruption of chromosome 21 gene expression, without a pervasive secondary effect on the remaining transcriptome. The identification of dysregulated genes and pathways suggests molecular changes that may underlie the Down syndrome phenotypes.

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    • "Several recent studies based on DNA microarray techniques concluded that an extra or missing chromosome may have a major effect on gene expression on the particular chromosome but only a minor effect on the whole transcriptome [4,8,9,19]. Conversely, some other studies suggested the extra or missing chromosome has a global effect on the whole transcriptome that is regulated by dosage compensation [20,21]. "
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    • "Global transcriptome profiling studies on prenatal samples of amniotic fluid and chorionic villi with trisomy of chromosome 21 [3,5] revealed significant dysregulation of HSA21 and non-HSA21 genes and concluded that resulting alterations reflect a combination of gene dosage effect and genome-wide transcriptional dysregulation hypotheses. Reports on transcriptomic analyses of other fetal tissues [4,6,10], including cerebellum, heart or fibroblasts demonstrated that sets of over-expressed and under-expressed genes differ across different cell types. In addition, data from global gene expression studies on postnatal samples with Ts21 [7-9], including adult human brain, lymphoblastoid cell line or fibroblasts showed a profile of up-regulation of HSA21 and dysregulation of non-HSA21 genes, consistent with the results of transcriptomic studies on Ts21 prenatal samples. "
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    PLoS ONE 09/2013; 8(9):e74184. DOI:10.1371/journal.pone.0074184 · 3.23 Impact Factor
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