Figure 8: Model. Stable repression at most cell cycle genes together with decommissioning of enhancers at rate-limiting cell cycle genes ensures robust cell cycle exit.

Cell cycle genes with simple enhancer architecture contain promoter proximal enhancers enriched for E2F binding sites that exhibit accessibility during proliferation as well as after cell cycle exit. These sites are dynamically occupied by activator or repressor complexes in a cell cycle phase-dependent manner in proliferative cells. After cell cycle exit, they are stably occupied by repressor complexes to maintain long-term repression. Rate-limiting cell cycle genes with complex, modular enhancer architecture exhibit enhancer decommissioning after the transition to a postmitotic state.