DEK promotes mammary hyperplasia and is associated with H3K27me3 epigenetic modifications

The DEK chromatin remodeling protein has oncogenic functions in breast cancers, but its functional role in normal mammary gland epithelium has remained unexplored. We developed two novel genetically engineered mouse models to study the role of Dek in normal mammary gland biology in vivo. Mammary gland-specific Dek transgenic mice developed hyperplasia and had a transcriptional profile that revealed increased expression of cell cycle, mammary stem/progenitor, and lactation-associated genes. Conversely, Dek knockout mice exhibited mammary gland functional defects resulting in dramatically reduced pup survival. Analysis of previously published scRNA-sequencing of mouse mammary glands revealed that Dek is most highly expressed in mammary stem cells and alveolar progenitor cells, supporting the observed phenotypes. Mechanistically, we discovered that Dek is a modifier of Ezh2 methyltransferase activity, up-regulating the levels of histone H3K27me3 to control gene transcription. Combined, this is the first report to show that Dek promotes proliferation of mammary epithelial cells via transcriptional deregulation of cell cycle genes, potentially via epigenetic mechanisms, in vivo.