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Epigenetic regulation of Nanog gene in embryonic stem and trophoblast stem cells

The Nanog and Oct‐4 genes are essential for maintaining pluripotency of embryonic stem (ES) cells and early embryos. We previously reported that DNA methylation and chromatin remodeling underlie the cell type‐specific mechanism of Oct‐4 gene expression. In the present study, we found that there is a tissue‐dependent and differentially methylated region (T‐DMR) in the Nanog up‐stream region. The T‐DMR is hypomethylated in ES cells, but is heavily methylated in trophoblast stem (TS) cells and NIH/3T3 cells, in which the Nanog gene is repressed. Furthermore, in vitro methylation of T‐DMR suppressed Nanog promoter activity in reporter assay. Chromatin immunoprecipitation assay revealed that histone H3 and H4 are highly acetylated, and H3 lysine (K) 4 is hypermethylated at the Nanog locus in ES cells. Conversely, histone deacetylation and H3‐K4 demethylation occurred in TS cells. Importantly, in TS cells, hypermethylation of H3‐K9 and ‐K27 is found only at the Nanog locus, not the Oct‐4 locus, indicating that the combination of histone modifications associated with the Nanog gene is distinct from that of the Oct‐4 gene. In conclusion, the Nanog gene is regulated by epigenetic mechanisms involving DNA methylation and histone modifications.