Myc orchestrates a regulatory network required for the establishment and maintenance of pluripotency.

Pluripotent stem cells (PSCs) are maintained by a complex regulatory network orchestrated by transcription factors, epigenetic modifiers and non-coding RNAs. Central to this regulatory network is the Myc family of transcription factors. Defining roles for Myc in PSCs has been problematic but recently, a number of reports have provided insight into this question. An emerging picture now places Myc as a key regulator of the cell cycle, genomic maintenance and general metabolic activity in PSCs through its ability to directly regulate large numbers of target genes and more indirectly through control of microRNAs. One of Myc's main roles is to repress the activity of genes required for differentiation such as the endoderm master regulator, GATA6. The general mechanism by which Myc activates target genes is well understood but a remaining major challenge is to understand how it represses gene activity. Here we discuss potential mechanisms for how Myc establishes and maintains the pluripotent state and incorporate proteomics data that supports a model where Myc acts as part of a regulatory network with epigenetic modifiers.