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Methylation Mesa define functional regulatory elements for targeted gene activation [4C]

ABSTRACT: DNA methylation regulates transcription, yet the demethylation of canonical elements like promoter CpG islands exhibits inconsistent correlations with gene activation. We hypothesized that causal regulatory elements are defined by biophysical hypersensitivity. Profiling 24 whole-genome bisulfite sequencing samples across diverse human and murine models, we identified Methylation Mesa, narrow (~45-300 bp), structurally conserved epigenetic regulatory elements. Mesa show enrichment in 5’UTRs and correlates transcriptional activation significantly better than canonical promoters. To prove causality, we developed CRISPR-DiR, an RNA-based targeted demethylation technology offering greater spatial precision, higher potency, and reduced toxicity compared to CRISPR-TET1. Focal demethylation of a Mesa, but not the proximal promoter, drove exponential CDKN2A (p16) reactivation and robust in vivo tumor suppression. We demonstrate that precise demethylation of a Mesa locus triggers localized demethylation, subsequent activating histone deposition, and long-range 3D chromatin rewiring. Thus, Methylation Mesa represent precise, causal epigenetic hubs, and CRISPR-DiR as a potent high-resolution tool, establishing a structural framework for biomarker discovery and targeted therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153563 | GEO | 2024/12/13

REPOSITORIES: GEO

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