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Identification of a DNA methylation signature in blood from subjects affected by Down syndrome

ABSTRACT: Down syndrome is characterized by a wide spectrum of clinical signs, which include cognitive and endocrine disorders and haematological abnormalities. Although it is well established that the causative defect of Down syndrome is the trisomy of chromosome 21, the molecular bases of Down syndrome phenotype are still largely unknown. We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 subjects affected by Down syndrome (DS), using their healthy relatives as controls (mothers and unaffected siblings). This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental (lifestyle) factors. The identified epigenetic signature of Down syndrome includes differentially methylated regions that, although enriched on chromosome 21, interest most of the other chromosomes and can be functionally linked to the developmental and haematological defects characteristic of the disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE52588 | GEO | 2015/03/03

SECONDARY ACCESSION(S): PRJNA230264

REPOSITORIES: GEO

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Project description:Background: Among full autosomal trisomies, only trisomies of chromosome 21 (Down syndrome, DS), 18 (Edward syndrome, ES) and 13 (Patau syndrome, PS) are compatible with postnatal survival. But the mechanisms, how a supernumerary chromosome disrupts the normal development and causes specific phenotypes, are still not fully explained. As an alternative to gene dosage effects due to the trisomic chromosome, a genome-wide transcriptional dysregulation has been postulated. The aim of this study was to define the transcriptional changes in trisomy 13, 18, and 21 during early fetal development in order to define whether (1) overexpression of genes of the trisomic chromosome contributes solely to the phenotype, if (2) all genes of the trisomic chromosome are upregulated similarly and whether the ratio of gene expression is in agreement with the gene dosis, (3) whether the different trisomies behave similarly in the characteristics of transcriptional dysregulation, and (4) whether transcriptional pattern can be potentially used in prenatal diagnosis. Methods: Using oligonucleotide microarrays (Affymetrix, U133 Plus 2.0), we analyzed whole genome expression profiles representing 54.000 probe sets in cultured amniocytes (AC) and chorion villus cells (CV) from pregnancies with a normal karyotype and with trisomies of human chromosomes 21, 18 and 13. Findings: We observed a low to moderate up-regulation for a subset of genes of the trisomic chromosomes. Transcriptional level of approximately 12-13 % of the supernumerary chromosome appeared similar to the respective chromosome pair in normal karyotypes. Expression values as well as the expression patterns of genes from the trisomic chromosome can distinguish the respective trisomic samples from euploid controls. A subset of chromosome 21-genes including the DSCR1-gene involved in fetal heart development was consistently up-regulated in different tissues (AC, CV) of trisomy 21 fetuses whereas only minor changes were found for genes of all other chromosomes. In contrast, in trisomy 13 and trisomy 18 vigorous downstream transcriptional changes were found. Interpretation: Global transcriptome analysis for autosomal trisomies 13, 18, and 21 supported a combination of the two major hypotheses. As several transcriptional pathways are altered, complex regulatory mechanisms are involved in the pathogenesis of autosomal trisomies. A genome-wide transcriptional dysregulation was predominantly observed in trisomies 13 and 18, whereas a more to chromosome 21 restricted expression alteration was found in trisomy 21. Keywords: Trisomy, Down syndrome, Patau syndrome, Edward syndrome, microarray, gene expression, amniocytes, chorion villus cells, gene dosage effect, DSCR1

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Identification of a DNA methylation signature in blood from subjects affected by Down syndrome

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