PT - JOURNAL ARTICLE AU - Enrique Carrillo de Santa Pau AU - Juliane Perner AU - David Juan AU - Simone Marsili AU - David Ochoa AU - Ho-Ryun Chung AU - Daniel Rico AU - Martin Vingron AU - Alfonso Valencia TI - Functional analysis and co-evolutionary model of chromatin and DNA methylation networks in embryonic stem cells AID - 10.1101/008821 DP - 2014 Jan 01 TA - bioRxiv PG - 008821 4099 - http://biorxiv.org/content/early/2014/09/06/008821.short 4100 - http://biorxiv.org/content/early/2014/09/06/008821.full AB - We have analyzed publicly available epigenomic data of mouse embryonic stem cells (ESCs) combining diverse next-generation sequencing (NGS) studies (139 experiments from 30 datasets with a total of 77 epigenomic features) into a homogeneous dataset comprising various cytosine modifications (5mC, 5hmC and 5fC), histone marks and Chromatin related Proteins (CrPs). We applied a set of newly developed statistical analysis methods with the goal of understanding the associations between chromatin states, detecting co-occurrence of DNA-protein binding and epigenetic modification events, as well as detecting coevolution of core CrPs. The resulting networks reveal the complex relations between cytosine modifications and protein complexes and their dependence on defined ESC chromatin contexts.A detailed analysis allows us to detect proteins associated to particular chromatin states whose functions are related to the different cytosine modifications, i.e. RYBP with 5fC and 5hmC, NIPBL with 5hmC and OGT with 5hmC. Moreover, in a co-evolutionary analysis suggesting a central role of the Cohesin complex in the evolution of the epigenomic network, as well as strong co-evolutionary links between proteins that co-locate in the ESC epigenome with DNA methylation (MBD2 and CBX3) and hydroxymethylation (TET1 and KDM2A).In summary, the new application of computational methodologies reveals the complex network of relations between cytosine modifications and epigenomic players that is essential in shaping the molecular state of ESCs.