The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis

Abstract

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10−8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.

DNA Methylation Alterations in Blood Cells of Toddlers with Down Syndrome

“…In addition, an overdosage of transcription factors located on chromosome 21, such as RUNX1 binding to the core element of many enhancers and promoters, may disturb the genome-wide pattern of the chromatin structure and DNA methylation [3,4]. Accordingly, significant genome-wide perturbations in DNA methylation in DS, in comparison to matched controls, have been revealed in various cells and tissues, such as placenta tissue [5], blood cells [6][7][8][9], buccal epithelial cells [10], and neural tissue [4,[11][12][13]. Genomewide DNA methylation alterations have been detected in individuals with DS at different developmental stages throughout the lifespan-specifically, at the prenatal [11,14] and early postnatal stages [7][8][9] and in adulthood [6,10,12].…”

“…Accordingly, significant genome-wide perturbations in DNA methylation in DS, in comparison to matched controls, have been revealed in various cells and tissues, such as placenta tissue [5], blood cells [6][7][8][9], buccal epithelial cells [10], and neural tissue [4,[11][12][13]. Genomewide DNA methylation alterations have been detected in individuals with DS at different developmental stages throughout the lifespan-specifically, at the prenatal [11,14] and early postnatal stages [7][8][9] and in adulthood [6,10,12]. A recent meta-analysis provided evidence that a number of loci and genes might be consistently implicated in epigenetic mechanisms of DS across tissues and developmental stages [3].…”

“…At least 25 such pan-tissue genes predominantly hypermethylated in DS have been identified [3] that are involved in a broad spectrum of biological processes and, above all, in transcription regulation, signal transduction, and neurodevelopment. Consequently, the current literature reporting on systematic genome-wide epigenetic perturbations in DS has shown that DNA methylation alterations may be implicated in multiple developmental impairments and disease phenotypes in DS, such as defects in immune system development and hematopoiesis [8], altered neurodevelopment and brain function [12], and cognitive impairments [10], among others.…”

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

“…Interestingly, loss of methylation was found to affect genes associated with developmental disorders, while gain of methylation was observed in key genes involved in haematopoiesis. Similarly, haematopoietic cells of DS newborns have differential methylation patterns at promoter/enhancer regions relative to non-DS newborns [33]. Specifically, the promoter regions of two genes involved in megakaryopoiesis (RUNX1 and FLI1) were found to be hypermethylated in DS samples [33].…”

“…Similarly, haematopoietic cells of DS newborns have differential methylation patterns at promoter/enhancer regions relative to non-DS newborns [33]. Specifically, the promoter regions of two genes involved in megakaryopoiesis (RUNX1 and FLI1) were found to be hypermethylated in DS samples [33].…”