Transcriptional shut-off of MAP kinase signaling enables pluripotency maintenance during diapause [ChIP-Seq]

Exposure of unicellular or multicellular organisms to adverse environmental conditions, including nutrient deprivation, may induce a state of suspended animation or diapause. We here report that broad repression of RNA Pol II-driven gene expression by inhibiting the BET family's bromodomain-containing proteins (BET) triggers diapause in mouse embryonic stem (ES) cells. The diapause ES cells upregulate a functionally linked group of genes encoding negative regulators of MAP kinase signaling (NRMKS), which play a crucial role in ES cell differentiation. The elevated NRMKS expression is a hallmark of cells exposed to distinct diapause-inducing conditions, including mTOR inhibition, and are required for the pluripotency maintenance during diapause. Mechanistically, inhibition of mTORC1/2 leads to rapid decline of the Capicua transcriptional repressor (CIC) at the NRMKS gene promoters, followed by rapid transcriptional NRMKS gene upregulation. The mTOR and BET-dependent transcriptional switch supporting the undifferentiated state of the diapause ES cells suggests a broader usage of this mechanism in maintaining the undifferentiated state of metabolically dormant stem- or stem-like cells in different tissues.