File:Representation of chromatin marks in critical genes during specification.jpg

English: Representation of chromatin marks in critical genes during specification. In undifferentiated ES cells germ layer specific genes are marked by bivalent domains containing H3K4 and H3K27 trimethylation. These particular modifications play a role in keeping these genes silenced but poised for activation during differentiation. Although the molecular mechanisms responsible for the presence of these marks are not known it is possible that the presence of transcription activators, like the self-renewal factors Oct4, Sox2 and Nanog, and transcriptional repressors like REST at the regulatory regions of the marked genes could explain the simultaneous presence of these unique dual marks. The process of mesodermal specification involves the action of signalling molecules that belong to the TGFβ, Wnt and FGF families, among others. These factors are responsible for the initiation of signalling cascades in the cell cytoplasm and activation of critical transcription factors that turn on the expression of mesodermal specific genes and turn off non-mesodermal genes. How these signals orchestrate the correct pattern of gene expression and repression at the molecular level is not clear. However, these signalling events will ultimately lead to changes in histone modifications and more specifically to the resolution of the bivalent domains at the regulatory regions of differentiation genes, resulting in H3K4 methylation only in active genes and H3K27 methylation only in repressed genes. A critical event for specification is the permanent silencing of self-renewal genes, which involves the removal of the H3K4 trimethylation mark and the acquirement of repressive marks like H3K27 and H3K9 trimethylation and DNA methylation. These changes might be caused by the down regulation of the self-renewal factor network itself during differentiation and the action of differentiation induced repressors like p53 or GCNF. Poised genes are shown in yellow, active genes in green and repressed genes in red.