A hypothetical trivalent epigenetic code that affects the nature of human ESCs.

It has been suggested that DNA methylation can work in concert with other epigenetic factors, leading to changes in cellular phenotypes. For example, DNA demethylation modifications producing 5-hydroxymethylcytosine (5hmC) are thought to interact with histone modifications to influence the acquisition of embryonic stem cell (ESC) potency. However, the mechanism by which this occurs is still unknown. Thus, we systematically analysed the co-occurrence of DNA and histone modifications at genic regions as well as their relationship with ESC-specific expression using a number of heterogeneous public datasets. From a set of 19 epigenetic factors, we found remarkable co-occurrence of 5hmC and H4K8ac, accompanied by H3K4me1. This enrichment was more prominent at gene body regions. The results were confirmed using data obtained from different detection methods and species. Our analysis shows that these marks work cooperatively to influence ESC-specific gene expression. We also found that this trivalent mark is relatively enriched in genes related with immunity, which is a bit specific in ESCs. We propose that a trivalent epigenetic mark, composed of 5hmC, H4K8ac and H3K4me1, regulates gene expression and modulates the nature of human ESCs as a novel epigenetic code.