Abstract
BackgroundTrisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood.ResultsHere, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in each of these cell types. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites (TFBSs), implicating a mechanism involving altered TFBS occupancy. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects.ConclusionsThese data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0827-6) contains supplementary material, which is available to authorized users.
Highlights
Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood
Non-supervised correlation clustering and principal component analysis (PCA) of the 450K data showed that the methylation data for each cell and tissue type clustered separately, consistent with the expected tissue-specificity of DNA methylation patterns (Figure S2 in Additional file 1)
DS-differential methylation (DM) in brain cells and T lymphocytes is not accounted for by age effects We asked whether any of the DS-specific differential methylation (DS-DM) loci identified from our case–control analysis (151 CpGs defined by p < 0.001; delta AVG_Beta > 0.15) were gestational age-dependent, and we found only two DS-DM CpGs overlapping with the age-dependent set (Table S11a in Additional file 2; Figure S13 in Additional file 1)
Summary
Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. A recent hypothesis invokes epigenetics — the extra chromosome 21 could act in trans to produce network perturbations within cells leading to epigenetic alterations, including changes in DNA methylation, which would propagate to daughter cells in developing. As groundwork for future studies, we apply whole genome bisulfite sequencing (WGBS) to DNA from mice engineered to carry sub-chromosomal duplications mimicking human Ts21 and show that the epigenetic signature of human DS brain cells is partly recapitulated in these mouse models
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