DNA and histone methylation patterns correlate with – and define – transcriptional activity of the genome. In particular, DNA hypomethylation is associated with active chromatin and generally thought to be permissive for gene transcription. However, this rule is not globally applicable, and Shinichi Morishita, Hiroyuki Takeda and colleagues (p. 2568) now identify a particular class of hypomethylated domains (HMDs) in pluripotent cells of the medaka fish that are associated with strong gene repression. These HMDs are characterised by their large size and strong H3K27me3 deposition, and are referred to as large K27HMDs. Notably, they are most commonly found surrounding promoters of key developmental transcription factors that are under strong transcriptional repression. These HMDs shorten in mature cells, where the genes are expressed, due to DNA hypermethylation in these regions. Importantly, the authors find that a significant proportion of large K27HMDs are conserved between medaka and human stem cells. Together, these data define a genomic feature – the large K27HMD – that may be responsible for ensuring that key developmental transcription factors are kept strongly repressed in pluripotent cells.