DNA Methylation Landscapes of Human Fetal Development

PLoS Genet. 2015 Oct 22;11(10):e1005583. doi: 10.1371/journal.pgen.1005583. eCollection 2015 Oct.

Abstract

Remodelling the methylome is a hallmark of mammalian development and cell differentiation. However, current knowledge of DNA methylation dynamics in human tissue specification and organ development largely stems from the extrapolation of studies in vitro and animal models. Here, we report on the DNA methylation landscape using the 450k array of four human tissues (amnion, muscle, adrenal and pancreas) during the first and second trimester of gestation (9,18 and 22 weeks). We show that a tissue-specific signature, constituted by tissue-specific hypomethylated CpG sites, was already present at 9 weeks of gestation (W9). Furthermore, we report large-scale remodelling of DNA methylation from W9 to W22. Gain of DNA methylation preferentially occurred near genes involved in general developmental processes, whereas loss of DNA methylation mapped to genes with tissue-specific functions. Dynamic DNA methylation was associated with enhancers, but not promoters. Comparison of our data with external fetal adrenal, brain and liver revealed striking similarities in the trajectory of DNA methylation during fetal development. The analysis of gene expression data indicated that dynamic DNA methylation was associated with the progressive repression of developmental programs and the activation of genes involved in tissue-specific processes. The DNA methylation landscape of human fetal development provides insight into regulatory elements that guide tissue specification and lead to organ functionality.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / growth & development
  • Adrenal Glands / metabolism
  • Amnion / growth & development
  • Amnion / metabolism
  • Cell Differentiation / genetics*
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Epigenesis, Genetic*
  • Female
  • Fetal Development / genetics*
  • Gene Expression Regulation, Developmental
  • Genome, Human
  • Humans
  • Muscle, Skeletal / growth & development
  • Muscle, Skeletal / metabolism
  • Organ Specificity / genetics
  • Pancreas / growth & development
  • Pancreas / metabolism
  • Pregnancy
  • Pregnancy Trimester, First / genetics
  • Pregnancy Trimester, Second / genetics
  • Promoter Regions, Genetic
  • Regulatory Sequences, Nucleic Acid

Associated data

  • GEO/GSE56515

Grants and funding

SMCdSL is supported by the Netherlands Organization for Scientific Research (NWO, ASPASIA 015.007.037, http://www.nwo.nl) and the Interuniversity Attraction Poles (IAP, P7/07, http://www.belspo.be); MSR and FC by the Bontius Stichting [PANCREAS] (http://www.bontiusstichting.nl); BTH and RCS by the European Union’s Seventh Framework Program IDEAL (FP7/2007-2011) under grant agreement No. 259679 (http://ec.europa.eu/research/health/medical-research/human-development-and-ageing/projectsfp7_en.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.