2026 年 51 巻 1 号 p. 37-53
In higher eukaryotic cells, genomic DNA is packaged into dynamic chromatin domains whose physical behavior is coupled to DNA transactions such as transcription and DNA repair. Although chromatin organization is altered in cancer, how oncogenic signals modulate chromatin dynamics over time remains unclear. To address this issue, we established a doxycycline-inducible carcinogenesis model in hTERT-immortalized human RPE-1 cells expressing HPV16 E6/E7, MYC(T58A), and KRAS(G12V) (EMR cells) and investigated chromatin behavior during oncogene-driven transformation. Upon induction, EMR cells displayed accelerated proliferation, loss of contact inhibition, anchorage-independent growth in soft agar, and tumor formation in nude mice. Using time-resolved single-nucleosome imaging to track local chromatin dynamics over days to weeks of oncogene induction, we found that local nucleosome motion was unchanged at 1–3 days, significantly increased at 5–7 days, and returned to parental levels by 4 weeks, despite sustained oncogene expression and stable malignant growth. To explore the basis of this transient increase, we quantified DNA damage, histone marks, and transcription. γH2AX foci were elevated in EMR cells, but ATM/ATR inhibition had only minor effects on local chromatin motion, indicating that the DNA damage response is not the principal driver. By contrast, H3/H4 acetylation and nascent RNA synthesis were upregulated specifically during the early window of enhanced dynamics, whereas the heterochromatin mark H3K9me3 decreased, consistent with transient chromatin loosening associated with increased transcription. These findings reveal a biphasic change in local chromatin dynamics during human oncogene-driven transformation and provide a physical and temporal framework for understanding how oncogenic pathways reorganize chromatin.
Key words: cancer, oncogenesis, single-nucleosome imaging, chromatin dynamics
