Epigenomic co-localization and co-evolution reveal a key role for 5hmC as a communication hub in the chromatin network of ESCs

Epigenetic communication through histone and cytosine modifications is essential for gene regulation and cell identity. Here, we propose a framework that is based on a chromatin communication model to get insight on the function of epigenetic modifications in ESCs. The epigenetic communication network was inferred from genome-wide location data plus extensive manual annotation. Notably, we found that 5-hydroxymethylcytosine (5hmC) is the most influential hub of this network, connecting DNA demethylation to nucleosome remodeling complexes and to key transcription factors of pluripotency. Moreover, an evolutionary analysis revealed a central role of 5hmC in the co-evolution of chromatin-related proteins. Further analysis of regions where 5hmC colocalizes with specific interactors shows that each interaction points to chromatin remodelling, stemness, differentiation or metabolism. Our results highlight the importance of cytosine modifications in the epigenetic communication of ESCs.