Holliday Holly, Roden Daniel, Junankar Simon, Wu Sunny Z, Baker Laura A, Krisp Christoph, Chan Chia-Ling, McFarland Andrea, Skhinas Joanna N, Cox Thomas R, Pal Bhupinder, Huntington Nicholas D, Ormandy Christopher J, Carroll Jason S, Visvader Jane, Molloy Mark P, Swarbrick Alexander
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW 2010, Australia.
iScience. 2021 Jan 20;24(2):102072. doi: 10.1016/j.isci.2021.102072. eCollection 2021 Feb 19.
Inhibitor of differentiation (ID) proteins dimerize with basic HLH (bHLH) transcription factors, repressing transcription of lineage-specification genes across diverse cellular lineages. ID4 is a key regulator of mammary stem cells; however, the mechanism by which it achieves this is unclear. Here, we show that ID4 has a cell autonomous role in preventing myoepithelial differentiation of basal cells in mammary organoids and . ID4 positively regulates proliferative genes and negatively regulates genes involved in myoepithelial function. Mass spectrometry reveals that ID4 interacts with the bHLH protein HEB, which binds to E-box motifs in regulatory elements of basal developmental genes involved in extracellular matrix and the contractile cytoskeleton. We conclude that high ID4 expression in mammary basal stem cells antagonizes HEB transcriptional activity, preventing myoepithelial differentiation and allowing for appropriate tissue morphogenesis. Downregulation of ID4 during pregnancy modulates gene regulated by HEB, promoting specialization of basal cells into myoepithelial cells.
分化抑制因子（ID）蛋白与碱性螺旋-环-螺旋（bHLH）转录因子形成二聚体，从而抑制多种细胞谱系中谱系特异性基因的转录。ID4是乳腺干细胞的关键调节因子；然而，其实现这一功能的机制尚不清楚。在此，我们表明ID4在阻止乳腺类器官中基底细胞向肌上皮细胞分化方面具有细胞自主作用。ID4正向调节增殖基因，负向调节参与肌上皮功能的基因。质谱分析表明，ID4与bHLH蛋白HEB相互作用，HEB可结合参与细胞外基质和收缩性细胞骨架的基底发育基因调控元件中的E盒基序。我们得出结论，乳腺基底干细胞中高表达的ID4拮抗HEB的转录活性，阻止肌上皮细胞分化并允许适当的组织形态发生。孕期ID4的下调调节了受HEB调控的基因，促进基底细胞特化为肌上皮细胞。
