Abstract
Down Syndrome (DS) is characterized by a wide spectrum of clinical signs, which include segmental premature aging of central nervous and immune systems. Although it is well established that the causative defect of DS is the trisomy of chromosome 21, the molecular bases of its phenotype are still largely unknown. We used the Infinium HumanMethylation450 BeadChip to investigate DNA methylation patterns in whole blood from 29 DS persons, using their relatives (mothers and unaffected siblings) as controls. This family-based model allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. Although differentially methylated regions (DMRs) displayed a genome-wide distribution, they were enriched on chromosome 21. DMRs mapped in genes involved in developmental functions, including embryonic development (HOXA family) and haematological (RUNX1 and EBF4) and neuronal (NCAM1) development. Moreover, genes involved in the regulation of chromatin structure (PRMD8, KDM2B, TET1) showed altered methylation. The data also showed that several pathways are affected in DS, including PI3K-Akt signaling. In conclusion, we identified an epigenetic signature of DS that sustains a link between developmental defects and disease phenotype, including segmental premature aging.
Highlights
Down Syndrome (DS) results from the presence of all or part of an extra copy of human chromosome 21 (HSA21) [1] and it is the most common aneuploidy in humans, with about 1 in 700 live births [2]
In this study we investigated the epigenetic status, in terms of DNA methylation, of white blood cells (WBC) from DS persons (DSP), in comparison with their mothers (DSM) and unaffected sibs (DSS)
Our analysis showed that DS is characterized by a profound rearrangement of genome-wide DNA methylation patterns
Summary
Down Syndrome (DS) results from the presence of all or part of an extra copy of human chromosome 21 (HSA21) [1] and it is the most common aneuploidy in humans, with about 1 in 700 live births [2]. DS is traditionally classified as a progeroid disease [5,6], as affected subjects exhibit precocious appearance of age-associated biomarkers like DNA damage accumulation and chromosomal instability [7,8,9,10]. Persons with DS suffer an accelerated decline of cognitive functions [14] and develop Alzheimer’s disease with high frequency [11]. DS persons present peculiar haematological abnormalities, that include abnormal platelet counts, macrocytosis, alterations in lymphocytes composition [17,18] and higher susceptibility to develop leukemia, including rare forms like acute megakaryoblastic leukemia, and other hematopoietic disorders [19,20,21]
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