Nuclear mTOR-Polycomb synergism at developmental gene promoters prone to activation

Abstract

Pluripotent cells hold the capacity to differentiate into cells with diverse functions, enabling development and regeneration. The balance between local epigenetic repression and maintaining the potential for prompt transcriptional activation supports pluripotency while allowing imminent differentiation. How the activation of developmental pathways is correctly timed in sync with the environment remains poorly understood. Here we find that the cellular growth regulator mTOR selectively binds developmental gene promoters in pluripotent mouse embryonic stem cells. mTOR binding at target genes correlates with and depends on histone H2AK119 monoubiquitination (H2AK119ub1) deposited by the Polycomb Repressor Complex 1 (PRC1). Acute depletion of the whole PRC1 complex or its catalytic activity leads to depletion of mTOR at target gene promoters, whereas forced PRC1 recruitment to an artificial site brings along mTOR. At target genes, mTOR colocalizes with components of the transcription machinery and we find that mTOR-bound genes are distinctly characterized by high levels of RNA Polymerase II pausing. Our findings reveal a role of mTOR in pluripotency regulation and highlight the tight crosstalk between gene regulatory and cell growth machineries in stem cells.