Identification of a DNA methylation signature in blood cells from persons with Down Syndrome

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.

Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome

“…Thus, consistent with a previous report, 14 the RUNX1 promoter appears congenitally hypermethylated in DS. The RUNX1 isoform transcribed from the P1 promoter is expressed predominantly in hematopoietic cells.…”

Mouse-based genetic modeling and analysis of Down syndrome

“…Genespecific alterations in CpG methylation were first detected in blood leukocytes from adults with DS when compared to the samples from control individuals. 52 The presence of such a DS-specific methylation profile was further supported by other studies on the samples isolated from Ts21 placentas, fibroblasts [53][54][55] and more recently neural tissues. 56 Interestingly, such a phenomenon was recapitulated in mouse models of DS, 56 providing a system for further exploring the processes and the consequences of DS-associated methylation alterations.…”

Trans-acting epigenetic effects of chromosomal aneuploidies: lessons from Down syndrome and mouse models

“…As shown in Figure 2, gains of methylation in the RUNX1 promoter/enhancer region are seen both in DS versus control T cells [59] and in DS versus control whole blood leukocytes [57]. This CpG hypermethylation, which based on bis-seq data, is heterogeneous from cell to cell, may be acting as a type of dosage compensation at the single cell level (which would be interesting to test in future experiments), but nonetheless there is net overexpression of RUNX1 mRNA in total DS T cells.…”