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

Area of Science:

• Molecular Biology
• Epigenetics
• Gene Regulation

Background:

• RNA Polymerase II (Pol2) forms chromatin clusters that integrate promoter and enhancer interactions for gene expression control.
• The distinct features differentiating classes of Pol2-mediated clusters are not well understood.

Purpose of the Study:

• To identify and characterize distinct classes of Pol2-mediated chromatin clusters.
• To investigate the role of CBP/p300 in regulating these clusters and associated gene expression.
• To understand the vulnerability of specific gene sets to CBP/p300 inhibition.

Main Methods:

• Identification of two distinct classes of Pol2-mediated clusters based on molecular features.
• Analysis of CBP/p300 occupancy, enhancer-promoter looping, and gene expression profiles.
• Acute inhibition of CBP/p300 catalytic activity and assessment of downstream effects.
• Integrative machine learning modeling to identify predictors of gene sensitivity to inhibition.

Main Results:

• Two distinct Pol2 cluster classes were identified: one associated with CpG islands and housekeeping genes, and another with CBP/p300, enhancer-promoter looping, and lineage-defining genes.
• CBP/p300 inhibition rapidly decreased enhancer acetylation and preferentially downregulated lineage-defining genes.
• Impaired cellular proliferation and activation of apoptotic programs were observed following CBP/p300 inhibition.
• Machine learning models identified cluster strength, RNA half-life, and CpG island content as key predictors of gene sensitivity to CBP/p300 inhibition.

Conclusions:

• These findings elucidate the distinct roles of Pol2-mediated clusters in gene regulation.
• The study clarifies the concept of enhancer-addiction and highlights the vulnerability of lineage-defining genes to CBP/p300 inhibition.
• Understanding these mechanisms provides insights into cellular responses to epigenetic perturbations.