Widespread domain-like perturbations of DNA methylation in whole blood of Down syndrome neonates

Abstract

IntroductionDown syndrome (DS) is the most frequent genetic cause of intellectual disability. Despite the fact that more than 50 years have passed since the discovery of its genetic aberrations, the exact pathogenesis of the DS phenotype has remained largely unexplained. It was recently hypothesized that the DS pathogenesis involves complex (epi)genetic, molecular and cellular determinants. To date, many reports have addressed epigenetic aberrations associated with DS at different developmental stages/ages and tissue types, but to our best knowledge not in DS newborns. This study aimed to investigate genome-wide methylation patterns in DS newborns compared to non-trisomic newborns.MethodWe analyzed blood samples obtained from ten newborns with DS and five age-matched non-trisomic newborns. Epigenetic profiles were obtained from extracted DNA using the Illumina Infinium 450K array. Since aberrant blood cell distribution is known to be present in DS, we applied two distinct models: with and without correction for estimated blood cell distribution.ResultsDifferentially methylated position (DMP) analysis of the uncorrected model detected 19525 significant hits (51,2% hypomethylated). In the corrected model, we found 121953 significant DMPs (49,8% hypomethylated). Independent of the used model we observed a chromosome 21 dosage effect. Moreover, we detected 46 and 145 differentially methylated regions in the uncorrected and corrected model respectively, both showing hypomethylation overrepresentation. Replication analyses of DMPs and DMRs found by Bacalini et al. (2015) showed a large overlap.ConclusionIn this study, we found methylation profile differences between DS newborns and controls reflecting a systematically affected epigenetic profile. The observed chromosome 21 dosage effect suggests the involvement of affected essential regulatory factors/regions or altered expression of chromatin modeling enzymes located on chromosome 21. Additional research is necessary to substantiate these hypotheses.

Age-related trajectories of DNA methylation network markers: a parenclitic network approach to a family-based cohort of patients with Down Syndrome

“…Among the different cohorts investigated so far, the GSE52588 dataset is a family-based cohort, which allows to evaluate not only the epigenetic remodelling in DS, but also the potential contribution of genetic background and environment, which are at least in part shared by the members of the same family 20 . DMPs and DMRs analysis on this dataset have highlighted epigenetic alterations in genes involved in developmental functions (including haematological and neuronal development), metabolic functions and regulation of chromatin structure, in line with the results on independent cohorts [20][21][22][23] .…”

“…As an application and demonstration of our implementation, we considered a publicly available dataset (GSE52588) in which whole blood DNA methylation was assessed by the Infinium HumanMethylation450 BeadChip in a cohort including persons affected by Down Syndrome (DS), their unaffected siblings (DSS) and their mothers (DSM) 20 (29 families in total). Previous studies have demonstrated that Down Syndrome (DS), which is caused by a full or partial trisomy of chromosome 21, is characterized by a profound remodelling of DNA methylation patterns, which involves not only chromosome 21 but is widespread across the genome [20][21][22][23] . Among the different cohorts investigated so far, the GSE52588 dataset is a family-based cohort, which allows to evaluate not only the epigenetic remodelling in DS, but also the potential contribution of genetic background and environment, which are at least in part shared by the members of the same family 20 .…”

DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors

“…We also identified hypomethylation of chromosomes 2, 8, 19, and 22 whereas chromosomes 6 were enriched and 17 depleted with hypermethylated probes. Uneven chromosomal distribution of DMPs has been observed across a variety of cells and tissues with T21 [14,15,46,47]. The reason for this is unclear and it may be hypothesized that the genomic imbalance in T21 affects the chromosomal organization in 3D, with distorted interactions between certain genomic regions, resulting in a skewing of the chromosomal and subchromosomal DNA methylation pattern.…”

New approaches to studying early brain development in Down syndrome

“…4,5 The phenotype in Down syndrome is thought to arise from the overexpression and dysregulation of these genes and their associated pathways, together with global cellular stress responses and compensatory mechanisms early in development. 6 Epigenetic changes have also been observed in the fetal brain and blood from newborn infants with Down syndrome 7,8 which may further impact development and contribute to the range of observed cognitive outcomes. The neurological phenotype constantly changes over the life span of Down syndrome, 9 with differences continuing into adulthood.…”