E2F1 induces a G0-G1 reentry transcriptional program without changing chromatin accessibility

Quiescent cells repress cell-cycle genes via chromatin-based mechanisms to maintain a non-dividing state, yet remain poised to reenter the cell cycle upon stimulation. E2F1, a canonical activator of cell-cycle genes, is sufficient to induce cell-cycle reentry from quiescence, but how it overcomes chromatin-mediated repression remains unclear. Here, we show that inducible E2F1 expression triggers exit from quiescence without changes in chromatin accessibility by harnessing regulatory elements with limited accessibility. Time-resolved transcriptomic analysis demonstrates that E2F1 induces an accelerated transcriptional program compared to serum stimulation. Unlike serum, which triggers broad chromatin remodeling, E2F1 activates genes within a chromatin context with limited accessibility. ChIP-seq analyses reveal that E2F1 binds target sites in quiescent cells to activate canonical cell-cycle genes. Biochemical reconstitution demonstrates that E2F1 binds nucleosomes and accesses DNA wrapped by histones. These findings suggest that E2F1 accesses nucleosome-associated DNA and initiates transcription without major chromatin reorganization. Our work redefines the relationship between transcription factor and chromatin dynamics during fate transitions and establishes E2F1 as a potent regulator capable of inducing cell-cycle reentry without changing chromatin accessibility.