HP1α depletion and TGFβ activation exert antagonistic effects on 3D genome organization.

However, how key factors like Heterochromatin Protein 1 alpha (HP1α) and Transforming Growth Factor beta (TGFβ) remodel this architecture to drive tumorigenesis remains poorly understood. We investigated the effects of HP1α knockdown and TGFβ treatment on higher-order chromatin structure and gene expression in human mammary epithelial cells.

Our findings reveal that HP1α depletion and TGFβ stimulation exert distinct and opposing effects on genome compartmentalization and subcompartmentalization. HP1α knockdown drives a genome-wide shift of chromatin from transcriptionally inactive B compartments to active A compartments. This is accompanied by a stepwise redistribution of A subcompartments toward the most transcriptionally active state (A3), and the upregulation of oncogenic genes involved in EMT and proliferation.