Abstract
BackgroundDown syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two DS patients with complete T21 and matched euploid donors into two distinct neural stages corresponding to early- and mid-gestational ages.ResultsUsing the Illumina Infinium 450K array, we assessed the DNA methylation pattern of known CpG regions and promoters across the genome in trisomic neural iPSC derivatives, and we identified a total of 500 stably and differentially methylated CpGs that were annotated to CpG islands of 151 genes. The genes were enriched within the DNA binding category, uncovering 37 factors of importance for transcriptional regulation and chromatin structure. In particular, we observed regional epigenetic changes of the transcription factor genes ZNF69, ZNF700 and ZNF763 as well as the HOXA3, HOXB3 and HOXD3 genes. A similar clustering of differential methylation was found in the CpG islands of the HIST1 genes suggesting effects on chromatin remodeling.ConclusionsThe study shows that early established differential methylation in neural iPSC derivatives with T21 are associated with a set of genes relevant for DS brain development, providing a novel framework for further studies on epigenetic changes and transcriptional dysregulation during T21 neurogenesis.
Highlights
Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21)
The DNA was obtained from Induced pluripotent stem cell (iPSC) derived neural progenitor cells (NPCs) [24], and further differentiated for 30 days (DiffNPC) using an undirected protocol ([10]; Fig. 1)
We identified 500 differentially methylated probes (DMPs), corresponding to approximately 0.1% of all CpGs queried by the array, that clustered together in the four trisomic samples at both stages of neural differentiation (Additional file 3)
Summary
Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). We and others have previously shown global gene expression changes in neural cells and brain specimens with T21 [5,6,7,8,9,10]. Prior studies of DNA-methylation patterns in pre- and postnatal brain specimens with T21, as well as in orthologous mice models, have shown alterations across the entire genome when compared to matched euploid tissues [14,15,16]. The same study showed enrichment for differentially CpG islands in DS brain samples [17] While these independent studies have brought important knowledge on epigenetic changes in developing and adult DS brains, the correlation to the global transcriptional changes remains elusive
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