Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation

B Gu, P Sun, Y Yuan, R. C Moraes, A Li, A Teng, A Agrawal, C Rheaume, V Bilanchone, J. M Veltmaat, K. I Takemaru, S Millar, E. Y. H.P Lee, M. T Lewis, B Li and X. Dai

The Journal of Cell Biology, 2009, 185(5), 811-826. DOI: 10.1083/jcb.200810133

Abstract

Recent studies have unequivocally identified multipotent stem/progenitor cells in mammary glands, offering a tractable model system to unravel genetic and epigenetic regulation of epithelial stem/progenitor cell development and homeostasis. In this study, we show that Pygo2, a member of an evolutionarily conserved family of plant homeo domain–containing proteins, is expressed in embryonic and postnatal mammary progenitor cells. Pygo2 deficiency, which is achieved by complete or epithelia-specific gene ablation in mice, results in defective mammary morphogenesis and regeneration accompanied by severely compromised expansive self-renewal of epithelial progenitor cells. Pygo2 converges with Wnt/β-catenin signaling on progenitor cell regulation and cell cycle gene expression, and loss of epithelial Pygo2 completely rescues β-catenin–induced mammary outgrowth. We further describe a novel molecular function of Pygo2 that is required for mammary progenitor cell expansion, which is to facilitate K4 trimethylation of histone H3, both globally and at Wnt/β-catenin target loci, via direct binding to K4-methyl histone H3 and recruiting histone H3 K4 methyltransferase complexes.

ASCI-ID: 1327-26