Abstract
Chromatin architecture plays a key role in development and cancer, yet most studies lack mechanistic depth due to widespread epigenomic remodeling. To address this, we tracked chromatin structure dynamics during the progression of endocrine resistance in ER+ breast cancer using Hi-C, chromatin accessibility, epigenomic, and transcriptomic profiling. We uncovered a critical role for H3K9 methylation and the demethylase KDM4C association with SWI/SNF in driving proliferation of cells fated to become resistant through a nongenomic estrogen-mediated mechanism. These findings highlight the mechanistic contribution of chromatin regulation in therapy resistance and offer a blueprint for studying similar processes in cancer, development, and cell fate decisions.