Acute degron-mediated RUNX1 loss reprograms enhancer activity associated with epithelial destabilization and initiation of cancer hallmarks [PRO-seq]

Mechanisms governing the dual roles of RUNX1 in sustaining the mammary epithelial phenotype while suppressing initiation of cancer-compromised gene expression are unclear. Degron-mediated acute, selective, and complete RUNX1 ablation in human mammary epithelial cells reveals promoter and distal enhancer-driven expression of a gene cohort.

RUNX1 ablation rapidly and selectively decreases chromatin accessibility and H3K27ac at RUNX1-bound enhancers, but not promoters. While differentially initiated and expressed genes contacted by RUNX1-bound enhancers are enriched in epithelial maintenance and stemness pathways, genes with RUNX1-promoter occupancy support DNA damage responsiveness. Modified cell morphology, metabolic control, breast cancer stemness, plasticity, anchorage-independent survival, chemoresistance, and perturbed DNA damage reactivity are observed upon RUNX1 ablation.