Hypothetical Model of ID Protein-Mediated Modulation of Polycomb Repressive Complex 2 in Lineage Specification and Tumorigenesis
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The Inhibitor of DNA-binding (ID) proteins are dominant-negative regulators of basic helix-loop-helix (bHLH) transcription factors, playing a pivotal role in cellular differentiation, proliferation, and lineage plasticity. The Polycomb Repressive Complex 2 (PRC2), through trimethylation of histone H3 at lysine 27 (H3K27me3), mediates long-term transcriptional repression essential for development and cancer. Here, we hypothesize that ID proteins indirectly modulate PRC2 recruitment and function by altering chromatin accessibility and transcription factor occupancy, particularly during transitions between stem-like and differentiated states. We propose a mechanistic model whereby ID proteins prime the chromatin landscape for PRC2 activity, promoting a permissive environment for epigenetic silencing in stem/progenitor populations and tumor cells. This functional support could cause phenotypic plasticity in cancer and offer novel epigenetic targets for therapeutic intervention.