Suzuki T. et al.
Hepatocytes are the dominant cell type in the human liver, with functions in metabolism, detoxification, and producing secreted proteins. Although gene regulation and master transcription factors involved in the hepatocyte differentiation have been extensively investigated, little is known about how the epigenome is regulated, particularly the dynamics of DNA methylation and the critical upstream factors. Here, by examining changes in the transcriptome and the methylome using an in vitro hepatocyte differentiation model, we show putative DNA methylation-regulating transcription factors, which are likely involved in DNA demethylation and maintenance of hypo-methylation in a differentiation stage-specific manner. Of these factors, we further reveal that GATA6 induces DNA demethylation together with chromatin activation in a binding-site-specific manner during endoderm differentiation. These results provide an insight into the spatiotemporal regulatory mechanisms exerted on the DNA methylation landscape by transcription factors and uncover an epigenetic role for transcription factors in early liver development.