Introduction 

Cell proliferation is fundamental to embryonic development, tissue maintenance, wound healing and recovery from injury. However, uncontrolled cell division can disrupt tissue homeostasis and contribute to tumour development. Most differentiated cells can enter a reversible non-proliferative state known as cellular quiescence (G0), in which proliferation-related genes remain suppressed while the capacity to re-enter the cell cycle is preserved. The transition between quiescence and proliferation is regulated by extracellular growth signals, cell-cycle regulatory proteins and transcriptional mechanisms.1,2 Dysregulation of these mechanisms is a characteristic feature of several cancers. 

The retinoblastoma (RB)-E2F signalling pathway is a central regulator of cell-cycle progression. Among its components, E2F1 acts as a transcription factor that activates genes involved in DNA replication and cell-cycle progression. Under normal conditions, RB proteins regulate E2F activity, preventing inappropriate cell-cycle entry. Disruption of this regulatory pathway can result in uncontrolled cellular proliferation and contribute to tumorigenesis.3,4 

E2F1-mediated activation of cell-cycle progression 

A recent study by Lodewijk et al., published in The EMBO Journal in November 2026, identified an alternative mechanism through which E2F1 promotes cell-cycle re-entry. Traditionally, quiescent cells were considered to require growth-factor stimulation to initiate chromatin remodelling, allowing transcription factors to access DNA and activate proliferation-associated genes. However, the researchers demonstrated that E2F1 could induce cell-cycle re-entry without substantial changes in global chromatin accessibility.5 

Using inducible E2F1 expression in quiescent mouse fibroblasts, the investigators demonstrated that increased E2F1 expression was sufficient to activate cell-cycle progression. E2F1 stimulated the expression of genes involved in cell-cycle regulation, including cyclins, and promoted progression through the G1, S and G2/M phases. Previous investigations had also demonstrated that E2F1 overexpression could induce DNA synthesis in growth-arrested cells, establishing its direct involvement in cell-cycle activation.6 

Chromatin accessibility and the pioneer-like activity of E2F1 

The most important finding was that E2F1 could activate cell-cycle genes without requiring extensive chromatin decondensation. Chromatin normally restricts access to DNA through the organisation of genetic material around histone proteins. During conventional growth-factor-mediated cell-cycle re-entry, chromatin accessibility increases, facilitating transcription factor binding and gene activation. 

In contrast, the recent study demonstrated that E2F1 could bind regulatory regions with limited pre-existing accessibility. Chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq) and biochemical nucleosome-reconstitution experiments demonstrated that E2F1 could directly interact with nucleosomes and access DNA sequences associated with histones.5 

This behaviour resembles the activity of pioneer transcription factors, which can recognise DNA sequences within relatively inaccessible chromatin. However, E2F1 differs from conventional pioneer factors because its activity does not produce widespread chromatin opening. Instead, it appears to activate selected cell-cycle genes through direct interaction with nucleosome-associated DNA. 

E2F1 expression threshold and cellular fate determination 

Another important observation was the relationship between E2F1 expression levels and cell-cycle re-entry. The investigators identified a threshold of E2F1 expression above which quiescent cells initiated proliferation. This suggests that E2F1 abundance may act as a regulatory determinant of cellular fate. Previous research has also demonstrated that E2F1 expression levels influence whether cells undergo proliferation or apoptosis, indicating that its biological effects are concentration-dependent.7 

Live-cell imaging further demonstrated that E2F1-induced cell-cycle re-entry occurred more rapidly than growth-factor-mediated re-entry. However, sustained E2F1 expression did not support unlimited proliferation. Most E2F1-expressing cells underwent one to three divisions during the observation period, with substantial cell death subsequently observed. These findings indicate that E2F1-mediated cell-cycle activation may operate differently from conventional growth-factor-dependent proliferation.5 

Implications for cancer development and therapeutic targeting 

The findings have important implications for understanding cancer biology. The RB-E2F pathway is frequently dysregulated in human malignancies, allowing cancer cells to overcome normal cell-cycle checkpoints and sustain inappropriate proliferation.3,4,8 Increased E2F1 activity may enable cells to activate proliferation-associated genes despite the presence of chromatin-mediated repression. 

The ability of E2F1 to access nucleosome-associated DNA without extensive chromatin remodelling provides a potential explanation for how cancer cells may overcome cellular quiescence. However, whether this mechanism is directly exploited by specific human cancers remains to be established. Furthermore, E2F1 has context-dependent functions, including the regulation of apoptosis and DNA damage responses, making its inhibition therapeutically challenging.7,8 

Future research should investigate the molecular interactions responsible for E2F1-mediated nucleosome binding, identify tumour subtypes dependent on this mechanism and evaluate approaches to selectively inhibit its transcriptional activity. Such investigations may provide opportunities for developing targeted strategies to interfere with aberrant cell-cycle activation. 

Conclusion 

The discovery of E2F1-mediated cell-cycle re-entry without substantial global chromatin remodelling provides new insights into the regulation of cellular proliferation. By directly accessing nucleosome-associated DNA, E2F1 can activate selected cell-cycle genes and promote cellular transitions from quiescence to proliferation. Although the therapeutic implications remain under investigation, understanding this mechanism may contribute to identifying novel molecular targets for cancer treatment. 

References  

1. Coller HA, Sang L, Roberts JM. A new description of cellular quiescence. PLoS Biol. 2006;4(3):e83. 
2. Marescal O, Cheeseman IM. Cellular mechanisms and regulation of quiescence. Dev Cell. 2020;55(3):259-271. 
3. Chen HZ, Tsai SY, Leone G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer. 2009;9(11):785-797. 
4. Fischer M, Müller GA. Cell cycle transcription control: DREAM/MuvB and RB-E2F complexes. Crit Rev Biochem Mol Biol. 2017;52(6):638-662. 
5. Lodewijk GA, Topacio BR, Lee S, Kozuki S, Alburo AAA, Williams Z, et al. E2F1 induces a G0-G1 reentry transcriptional program without changing chromatin accessibility. EMBO J. Published online November 6, 2026. 
6. Johnson DG, Schwarz JK, Cress WD, Nevins JR. Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature. 1993;365(6444):349-352. 
7. Shats I, Deng M, Davidovich A, Zhang C, Kwon JS, Manandhar D, et al. Expression level is a key determinant of E2F1-mediated cell fate. Cell Death Differ. 2017;24(4):626-637. 
8. Roworth AP, Ghari F, La Thangue NB. To live or let die – complexity within the E2F1 pathway. Mol Cell Oncol. 2015;2(1):e970480.