1.4 Bivalent promoters Several specific genomic regions (domains) have been conferred in ESC studies that have different histone modifications, such as H3K4me3 (active) and H3K27me3 (silenced) in the promoters or H3K4me1 and H3K27ac in active enhancers (Zhou et al. 2011). The distinct chromatin activating (H3K4me3) and repressing (H3K27me3) signals observed in the promoters of several developmentally regulated genes were given the name “bivalent” marks and appeared to correlate most strongly with developmental gene promoters in ESCs (B. Bernstein et al. 2006). The key point in the study by Bernstein et al. (2006), were the highly conserved noncoding elements (HCNEs), which had apparently been found in the vicinity of genes encoding developmental transcription factors (B. Bernstein et al. 2006). They used the technique of chromatin immunoprecipitation (ChIP) and processing arrays (ChIP-chip), studying the patterns of coexisting H3K4me3/H3K27me3 marks in HCNEs in mouse ESCs (mESCs). They performed a sequential ChIP, which tested the promoters of some genes that simultaneously presented the "mutually exclusive" marks until then, H3K4me3 and H3K27me3. Using sequential ChIP, the coexistence of H3K4me3 and H3K27me3 has long been established (Stock et al. 2007), as there are many arguments about the validity of bivalent domains. It is discussed that the detected bivalence simply reflects an average signal of heterogeneous cell populations exhibiting the signature of activation or silencing (Voigt et al. 2013). According to Bernstein et al. (2006), bivalent domains tend to be a feature of ESCs, because during differentiation, promoters of developmental genes that were occupied by both marks, are occupied by both... half of the article... .Zhang , Xing et al., 2003. Structural basis for the product specificity of histone lysine methyltransferases. Molecular Cell, 12(1), pp.177–185. Available at: http://dx.doi.org/10.1016/S1097-2765(03)00224-7. Zhang, Yubo et al., 2013. Chromatin connectivity maps reveal dynamic long-range promoter- enhancer. Nature, 504(7479), pp.306–310. Available at: http://dx.doi.org/10.1038/nature12716.Zhao, XD et al., 2007. Genome-wide mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in embryonic stem cells human. Cellular Stem Cell, 1(3), pp.286–298. Available at: http://dx.doi.org/10.1016/j.stem.2007.08.004.Zhou, V., Goren, A. & Bernstein, B., 2011. Graphical representation of histone modifications and functional organization of mammalian genomes. Nature reviews. Genetics, 12(1), pp.7–18. Available at: http://dx.doi.org/10.1038/nature09692.