Lineage-specific interface proteins match up the cell cycle and differentiation in embryo stem cells

•Genes regulated in cell cycle and embryonic stem cell differentiation overlap.•The relation of cell cycle and embryonic stem cell differentiation is fate-specific.•Cell cycle and embryonic stem cell differentiation are linked by interface genes.•The interface proteins are enriched in unanticipated functionalities.•The interface proteins are post-transcriptionally regulated.

The shortage of molecular information on cell cycle changes along embryonic stem cell (ESC) differentiation prompts an in silico approach, which may provide a novel way to identify candidate genes or mechanisms acting in coordinating the two programs. We analyzed germ layer specific gene expression changes during the cell cycle and ESC differentiation by combining four human cell cycle transcriptome profiles with thirteen in vitro human ESC differentiation studies. To detect cross-talk mechanisms we then integrated the transcriptome data that displayed differential regulation with protein interaction data. A new class of non-transcriptionally regulated genes was identified, encoding proteins which interact systematically with proteins corresponding to genes regulated during the cell cycle or cell differentiation, and which therefore can be seen as interface proteins coordinating the two programs. Functional analysis gathered insights in fate-specific candidates of interface functionalities. The non-transcriptionally regulated interface proteins were found to be highly regulated by post-translational ubiquitylation modification, which may synchronize the transition between cell proliferation and differentiation in ESCs.