Polycomb Marked Promoter Methylation Gains in Aging and Cancer are Independent of Replication
- 1Johns Hopkins University (School of Medicine)
Abstract
DNA methylation alterations are hallmark features of aging and cancer, occurring early during tumor initiation. Yet how these changes evolve during early tumorigenesis, and whether oncogenic signaling actively drives them, remains poorly understood due to limitations in resolving this at the longitudinal and clonal level. Here we developed a genome-wide DNA methylation profiling method for low DNA amounts and applied it to single stem cell-derived clones from a BRAFV600E -inducible mouse colon organoid model, tracking nucleotide-level methylation heterogeneity over time. BRAFV600E induction produced stepwise methylation divergence consistent with progressive clonal takeover, in contrast to gradual epigenetic drift in uninduced controls. Strikingly, while the specific CpG sites altered differed between BRAFV600E and control lineages, they converged on the same genomic elements. Particularly, Polycomb-marked promoter CpG-island methylation gains were not induced or accelerated by BRAFV600E, challenging models in which oncogenic signaling or cell proliferation actively instructs de novo methylation of Polycomb-targeted promoters. Instead, these gains tracked with "biological aging" independent of replication, which was validated across independent aging, cancer, and cell-line datasets. BRAFV600E -induced clones additionally showed progressive loss of intestinal lineage-specification transcription factor programs, consistent with selection for cells adapted to oncogenic stress. Together, these findings show that epigenetic trajectories during early tumor development, are rooted in baseline, age-dependent drivers of epigenetic alterations, and that oncogenic signaling acts primarily by selecting and expanding clones bearing pre-existing, age-associated epigenetic drift rather than instructing new methylation. Our findings have implications for how promoter methylation is interpreted as a cancer biomarker and for identifying upstream aging-associated processes as targets for early intervention.
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BibTeX
@misc{easwaran2026polycomb,
title = {{Polycomb Marked Promoter Methylation Gains in Aging and Cancer are Independent of Replication}},
author = {H. Easwaran and S.-J. Thursby and N. Patel and Z. Jin and J. Blum and S. Bisht and Y. Tao and Y. Bhandari and D. Petkovich and H. Ro and L. Yang and J. R. Wang and T. Pisanic and S. B. Baylin},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.763235},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.763235v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Polycomb Marked Promoter Methylation Gains in Aging and Cancer are Independent of Replication
AU - H. Easwaran
AU - S.-J. Thursby
AU - N. Patel
AU - Z. Jin
AU - J. Blum
AU - S. Bisht
AU - Y. Tao
AU - Y. Bhandari
AU - D. Petkovich
AU - H. Ro
AU - L. Yang
AU - J. R. Wang
AU - T. Pisanic
AU - S. B. Baylin
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.763235
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.763235v1
AB - DNA methylation alterations are hallmark features of aging and cancer, occurring early during tumor initiation. Yet how these changes evolve during early tumorigenesis, and whether oncogenic signaling actively drives them, remains poorly understood due to limitations in resolving this at the longitudinal and clonal level. Here we developed a genome-wide DNA methylation profiling method for low DNA amounts and applied it to single stem cell-derived clones from a BRAFV600E -inducible mouse colon organoid model, tracking nucleotide-level methylation heterogeneity over time. BRAFV600E induction produced stepwise methylation divergence consistent with progressive clonal takeover, in contrast to gradual epigenetic drift in uninduced controls. Strikingly, while the specific CpG sites altered differed between BRAFV600E and control lineages, they converged on the same genomic elements. Particularly, Polycomb-marked promoter CpG-island methylation gains were not induced or accelerated by BRAFV600E, challenging models in which oncogenic signaling or cell proliferation actively instructs de novo methylation of Polycomb-targeted promoters. Instead, these gains tracked with "biological aging" independent of replication, which was validated across independent aging, cancer, and cell-line datasets. BRAFV600E -induced clones additionally showed progressive loss of intestinal lineage-specification transcription factor programs, consistent with selection for cells adapted to oncogenic stress. Together, these findings show that epigenetic trajectories during early tumor development, are rooted in baseline, age-dependent drivers of epigenetic alterations, and that oncogenic signaling acts primarily by selecting and expanding clones bearing pre-existing, age-associated epigenetic drift rather than instructing new methylation. Our findings have implications for how promoter methylation is interpreted as a cancer biomarker and for identifying upstream aging-associated processes as targets for early intervention.
ER -