FoxA-dependent demethylation of DNA initiates epigenetic memory of cellular identity

Tissue-specific DNA methylation patterns are created by transcription factors that recruit methylation and demethylation enzymes to cis-regulatory elements. To date, it is not known whether transcription factors are needed to continuously maintain methylation profiles in development and mature tissues or whether they only establish these marks during organ development. We queried the role of the pioneer factor FoxA in generating hypomethylated DNA at liver enhancers. We discovered a set of FoxA-binding sites that undergo regional, FoxA-dependent demethylation during organ development. Conditional ablation of FoxA genes in the adult liver demonstrated that continued FoxA presence was not required to maintain the hypomethylated state, even when massive cell proliferation was induced. This study provides strong evidence for the stable, epigenetic nature of tissue-specific DNA methylation patterns directed by lineage-determining transcription factors during organ development. Reizel et al. demonstrate that FoxA transcription factors are necessary to generate low DNA methylation patterns at tissue-specific enhancers during embryonic development in vivo but are dispensable for their maintenance in adulthood. This finding demonstrates the stable nature of tissue-specific DNA methylation patterns that help to maintain tissue identity.