E2F1 induces a G0-G1 reentry transcriptional program without changing chromatin accessibility
Quiescent cells actively repress cell-cycle genes via chromatin-based mechanisms to maintain a non-dividing state, yet remain poised to reenter upon stimulation. E2F1, a canonical activator of cell-cycle genes, is sufficient to induce reentry from quiescence, but how it overcomes chromatin-mediated repression remains unclear. Here, we show that inducible E2F1 expression triggers exit from quiescence and progression through the cycle without changes in chromatin accessibility, by harnessing regulatory elements with limited, pre-existing accessibility. Using time-resolved transcriptomics, we demonstrate that E2F1 induces an accelerated transcriptional program compared to serum. Unlike serum, which triggers broad chromatin remodeling, E2F1-induced activation occurs in a context of limited accessibility. ChIP-seq reveals that E2F1 directly binds target sites in quiescent cells to upregulate canonical genes. Biochemical reconstitution shows that E2F1 binds nucleosomes and accesses internal E2F sites within histone-wrapped DNA. These findings suggest that E2F1 can engage nucleosome-associated DNA and initiate transcription without major chromatin reorganization, redefining transcription factor-chromatin dynamics during cell fate transitions and establishing E2F1 as a potent regulator of cell-cycle reentry.
Authors
- Gerd A. Müller (ORCID: https://orcid.org/0000-0002-4967-2487)
- Neda Hajiakhoond Bidoki (ORCID: https://orcid.org/0000-0002-6741-6735)
- Eric Malekos (ORCID: https://orcid.org/0000-0003-3084-2930)
- Abolfazl Zargari
- Benjamin R. Topacio (ORCID: https://orcid.org/0000-0002-2587-018X)
- Seth M. Rubin (ORCID: https://orcid.org/0000-0002-1670-4147)
- Gerrald A. Lodewijk (ORCID: https://orcid.org/0000-0002-4143-0432)
- Vanessa D. Jönsson (ORCID: https://orcid.org/0000-0002-6732-9607)
- Joscha Weiss (ORCID: https://orcid.org/0000-0002-4149-0478)
- Nicolas H. Thomä (ORCID: https://orcid.org/0000-0003-2685-906X)
- S. Ali Shariati (ORCID: https://orcid.org/0000-0002-3650-4820)
- Sayaka Kozuki (ORCID: https://orcid.org/0000-0002-6561-5781)
- Seung‐Ho Lee (ORCID: https://orcid.org/0000-0001-6958-7581)
- Clara J. Han (ORCID: https://orcid.org/0009-0007-0208-4139)
- Silvart Arabian
- Neda Bidoki
- Znala Williams (ORCID: https://orcid.org/0000-0003-4707-6021)
- Alexis Abigail A Alburo (ORCID: https://orcid.org/0009-0000-2911-9660)
- Edward Wu
Institutions
- University of California, Santa Cruz (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Friedrich Miescher Institute (CH)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-11-06
- DOI
- https://doi.org/10.1038/s44318-026-00936-4
- Citations
- 1
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 1.47
Funders
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institutes of Health
- National Cancer Institute
- National Institute of General Medical Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development