This is an important milestone paper in stem cell research in that the gene that was initially discovered in oral cancer development in the hamster cheek pouch model (DOC-1, CDK2AP1) is now a regulator of guiding the landing of the nucleosome remodeling complex (NuDR) to master stem cell genes in the WNT signaling pathway. This paper provides comprehensive biological interactions among NuRD, Wnt signalling, and mESC differentiation in a global genomic context. The interaction map uncovers new gene coexpression patterns, which modulate stem cell pluripotency. Taken together, we propose a model that there is an essential auxiliary component, CDK2AP1, that aids the association of the NuRD complex to specific promoters and mediate epigenetic regulation of regions of importance in controlling genes responsible for stem cell pluripotency.

Previously, others have shown the role of Wnt and p-β-catenin in stem cell pluripotency and differentiation potential. In fact, there have been controversies surrounding the exact role that Wnt may play in ESCs. Here, we have demonstrated that maintenance of mESC pluripotency is under epigenetic control of the Wnt pathway. Moreover, we observed the site- specific role of MBD3 with a complex interplay of CDK2AP1 on the promoters of Wnt singling genes. We also presented for the first time unique gene signatures responsible in Wnt signalling, differentiation, and nucleosome remodelling useful in defining the biological pathways involved in stem cell identity. We believe elucidating this link between NuRD, Wnt, and differentiation may enable us to ultimately control self-renewal in embryonic stem cells. Furthermore, understanding Wnt controlled stem cell pluripotency and the role of CDK2AP1-MBD3-NuRD complex at the molecular level may largely contribute to current knowledge of basic stem cell biology as well as future application to regenerative therapies.