Oct4 Nanog and Sox2 constitute a core of transcription factors controlling pluripotency Differentiation and reprogramming studies have unraveled a few epigenetic modifications associated in relation to the expression state of OCT4,,NANOG and SOX2. There is, however. no comprehensive map of chromatin states on these genes in human primary cells at different stages of differentiation We report here a profile of DNA methylation and of 10 histone modifications on regulatory regions of OCT4. NANOG and SOX2 in embryonal carcinoma cells, mesenchymal stern cells and fibroblasts. Bisulfite sequencing reveals correlation between promoter CpG methylation and repression of OCT4. but not NANOG or SOX2, suggesting distinct repression mechanisms Whereas none of these genes, even when inactive, harbor repressive trimethylated H3K9, CpG hypomethylated NANOG and SOX2, but not CpG methylated OCT4, are enriched in repressive H3K27me3 H3K79me1 and H3K79me3 tend to parallel each other and are linked to repression Moreover, we highlight an inverse relationship between H3K27me3 occupancy on promoters and H3K36me3 occupancy on coding regions of OCT4, NANOG and SOX2. Suggesting a cross-talk between K27 and K36 methylation. Establishment of distinct repression mechanisms for pluripotency-associated genes may constitute a safeguard system to prevent promiscuous reactivation during development or differentiation (C) 2009 Elsevier Inc All rights reserved.