Global DNA hypermethylation in down syndrome placenta

PLoS Genet. 2013 Jun;9(6):e1003515. doi: 10.1371/journal.pgen.1003515. Epub 2013 Jun 6.

Abstract

Down syndrome (DS), commonly caused by an extra copy of chromosome 21 (chr21), occurs in approximately one out of 700 live births. Precisely how an extra chr21 causes over 80 clinically defined phenotypes is not yet clear. Reduced representation bisulfite sequencing (RRBS) analysis at single base resolution revealed DNA hypermethylation in all autosomes in DS samples. We hypothesize that such global hypermethylation may be mediated by down-regulation of TET family genes involved in DNA demethylation, and down-regulation of REST/NRSF involved in transcriptional and epigenetic regulation. Genes located on chr21 were up-regulated by an average of 53% in DS compared to normal villi, while genes with promoter hypermethylation were modestly down-regulated. DNA methylation perturbation was conserved in DS placenta villi and in adult DS peripheral blood leukocytes, and enriched for genes known to be causally associated with DS phenotypes. Our data suggest that global epigenetic changes may occur early in development and contribute to DS phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosomes, Human, Pair 21 / genetics
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • DNA-Binding Proteins / genetics
  • Dioxygenases
  • Down Syndrome / genetics*
  • Down Syndrome / metabolism
  • Epigenesis, Genetic / genetics*
  • Female
  • Gene Expression Regulation
  • Humans
  • Male
  • Mixed Function Oxygenases
  • Placenta / cytology
  • Placenta / metabolism*
  • Pregnancy
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / genetics
  • Repressor Proteins / genetics
  • Sequence Analysis, DNA

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Mixed Function Oxygenases
  • TET1 protein, human
  • Dioxygenases
  • TET2 protein, human

Grants and funding

CD and GSHY were supported by a Bench to Bedside grant (09/1/50/19/622) from BMRC-NMRC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.