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

Michael J G Milevskiy; Hannah D Coughlan; Serena R Kane; Timothy M Johanson; Somayeh Kordafshari; Wing Fuk Chan; Minhsuang Tsai; Elliot Surgenor; Stephen Wilcox; Rhys S Allan; Yunshun Chen; Geoffrey J Lindeman; Gordon K Smyth; Jane E Visvader

doi:10.1016/j.xgen.2023.100424

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

Cell Genom. 2023 Oct 16;3(11):100424. doi: 10.1016/j.xgen.2023.100424. eCollection 2023 Nov 8.

Authors

Michael J G Milevskiy^{1

2}, Hannah D Coughlan^{2

3}, Serena R Kane^{1

2}, Timothy M Johanson^{2

4}, Somayeh Kordafshari^{1

2}, Wing Fuk Chan^{2

4}, Minhsuang Tsai^{1

2}, Elliot Surgenor¹, Stephen Wilcox⁵, Rhys S Allan^{2

4}, Yunshun Chen^{1

2

3}, Geoffrey J Lindeman^{1

6

7}, Gordon K Smyth^{3

8}, Jane E Visvader^{1

2}

Affiliations

¹ ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
² Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
³ Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁴ Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁵ Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁶ Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3010, Australia.
⁷ Parkville Familial Cancer Centre and Department of Medical Oncology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC 3050, Australia.
⁸ School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC 3010, Australia.

Abstract

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.

Keywords: chromatin looping; enhancer; epigenetics; mammary gland; polycomb; stem cells; transcription factors.