Cell differentiation results from coordinated changes in gene transcription in response to combinations of signals. FGF, Wnt, and mTOR signals regulate the differentiation of pluripotent mammalian cells towards embryonic and extraembryonic lineages, but how these signals cooperate with general transcriptional regulators is not fully resolved. Here, we report a genome-wide CRISPR screen that reveals both signaling components and general transcriptional regulators for differentiation-associated gene expression in mESCs. Focusing on the Mediator subunit Med12 as one of the strongest hits in the screen, we show that it regulates gene expression in parallel to FGF and mTOR signals. Loss of Med12 is compatible with differentiation along both the embryonic epiblast and the extraembryonic primitive endoderm lineage, but pluripotency transitions are slowed down, and the transcriptional separation between epiblast and primitive endoderm identities is enhanced in Med12 -mutant cells. These cellular phenotypes correlate with reduced biological noise upon loss of Med12 . These findings suggest that Med12 regulates cellular plasticity through the priming of transcriptional changes during differentiation, thereby modulating the effects of a broad range of signals.