Abstract
Epigenetic communication through histone and cytosine modifications is essential for gene regulation and in defining cell identity. Among the possible cytosine modifications, 5-hydroxymethylcytosine (5hmC) has been related with the pluripotent status of ESCs, although its precise functional role remains unclear. To fully understand the functional role of epigenetic modifications, it is necessary to analyze the whole chromatin network. Here, we propose a framework that is based on a communication model in which histone and cytosine modifications are considered epigenetic signals, while chromatin-associated proteins (CrPs) can act as emitters or receivers of these signals. We inferred the epigenetic communication network of mouse ESCs from genome-wide location data (77 different epigenomic features) combined with extensive manual annotation of epigenetic emitters and receivers based on the literature. Notably, 5hmC represents the most central hub of this network, connecting DNA demethylation to most of the nucleosome remodeling complexes and to several key transcription factors of pluripotency. An evolutionary analysis of the network revealed that most co-evolving CrP pairs are connected by 5hmC. Further analysis of the genomic regions marked with 5hmC and bound by specific interactors (ESRRB, LSD1, TET1 and OGT) shows that each interaction points to different aspects of chromatin remodeling, cell stemness, differentiation and metabolism. Taken together, our results highlight the essential role of cytosine modifications in the epigenetic communication of ESCs.