Polycomb Marked Promoter Methylation Gains in Aging and Cancer are Independent of Replication

Polycomb-marked promoter CpG-island methylation gains in a BRAFV600E-inducible mouse colon organoid model track with biological aging and are not induced or accelerated by BRAFV600E.

• Why it matters: Early tumorigenesis methylation changes are linked to aging and cancer, but it is unclear whether oncogenic signaling actively instructs them or whether age-linked drift is selected during clonal expansion.
• What they did: The study profiled genome-wide, nucleotide-level DNA methylation in single stem cell-derived clones over time using low-input methods, comparing BRAFV600E-induced versus uninduced organoid controls.
• The result: BRAFV600E caused stepwise methylation divergence consistent with clonal takeover, yet Polycomb promoter gains followed age-associated trajectories independent of replication, validated across independent aging, cancer, and cell-line datasets.

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