Hyung Joo Lee1,2, Rebecca F. Lowdon1,2, Brett Maricque1,2, Bo Zhang1,2, Michael Stevens1,2, Daofeng Li1,2, Stephen L. Johnson1 & Ting Wang1,2
1 Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA. 2 Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Correspondence to: Ting Wang
DNA methylation undergoes dynamic changes during development and cell differentiation. Recent genome-wide studies discovered that tissue-specific differentially methylated regions (DMRs) often overlap tissue-specific distal cis-regulatory elements. However, developmental DNA methylation dynamics of the majority of the genomic CpGs outside gene promoters and CpG islands has not been extensively characterized. Here, we generate and compare comprehensive DNA methylome maps of zebrafish developing embryos. From these maps, we identify thousands of developmental stage-specific DMRs (dsDMRs) across zebrafish developmental stages. The dsDMRs contain evolutionarily conserved sequences, are associated with developmental genes and are marked with active enhancer histone posttranslational modifications. Their methylation pattern correlates much stronger than promoter methylation with expression of putative target genes. When tested in vivo using a transgenic zebrafish assay, 20 out of 20 selected candidate dsDMRs exhibit functional enhancer activities. Our data suggest that developmental enhancers are a major target of DNA methylation changes during embryogenesis.