Three-dimensional genome architecture coordinates key regulators of lineage specification in mammary epithelial cells

Although lineage-specific genes have been identified in the mammary gland, little is known about the contribution of the 3D genome organization to gene regulation in the epithelium. Here, we describe the chromatin landscape of the three major epithelial subsets through integration of long-and short-range chromatin interactions, accessibility, histone modifications, and gene expression. While basal genes display exquisite lineage specificity via distal enhancers, luminal-specific genes show widespread promoter priming in basal cells. Cell specificity in luminal progenitors is largely mediated through extensive chromatin interactions with super enhancers in gene-body regions in addition to interactions with polycomb silencer elements. Moreover, lineage-specific transcription factors appear to be controlled through cell-specific chromatin interactivity. Finally, chromatin accessibility rather than interactivity emerged as a defining feature of the activation of quiescent basal stem cells. This work provides a comprehensive resource for understanding the role of higher-order chromatin interactions in cell-fate specification and differentiation in the adult mouse mammary gland.

Automated summary

This study provides a comprehensive analysis of the chromatin landscape of epithelial subsets in the mammary gland, revealing the contribution of 3D genome organization to gene regulation in the epithelium. The results demonstrate that lineage-specific genes exhibit lineage specificity through distal enhancers, while luminal-specific genes display promoter priming in basal cells. Chromatin interactions with super enhancers and polycomb silencer elements play a major role in the cell specificity of luminal progenitors.