CpG island density predicts CBP/p300 dependency across 3D chromatin clusters

RNA Polymerase II (Pol2) organizes transcription through higher-ordered chromatin clusters that integrate promoter and enhancer interactions to coordinate gene expression. Nevertheless, the features that distinguish unique classes of Pol2-mediated clusters remain to be defined. Here, we identify two distinct classes of Pol2-mediated clusters: one enriched for CpG islands, promoter-promoter interactions, and housekeeping gene expression, and another characterized by high CBP/p300 occupancy, enhancer-promoter looping, and lineage-defining (LD) transcriptional programs. Acute inhibition of CBP/p300 catalytic activity leads to rapid loss of acetylation at enhancers and preferential downregulation of LD genes, resulting in impaired cellular proliferation and activation of apoptotic programs. Integrative machine learning modeling reveals that cluster strength, RNA half-life, and CpG island content as strong predictors of genes sensitive to CBP/p300 inhibition. Together, these findings clarify enhancer-addiction and vulnerability to CBP/p300 inhibition.