1. Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation.
- Author
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Gu B, Sun P, Yuan Y, Moraes RC, Li A, Teng A, Agrawal A, Rhéaume C, Bilanchone V, Veltmaat JM, Takemaru K, Millar S, Lee EY, Lewis MT, Li B, and Dai X
- Subjects
- Animals, Cell Cycle, Cell Proliferation, Gene Expression Regulation, Histone Methyltransferases, Histone-Lysine N-Methyltransferase, Humans, Intracellular Signaling Peptides and Proteins metabolism, Lysine metabolism, Mammary Glands, Animal cytology, Mammary Glands, Animal growth & development, Mammary Glands, Animal metabolism, Methylation, Mice, Phenotype, Wnt Proteins genetics, Wnt Proteins metabolism, beta Catenin genetics, beta Catenin metabolism, Histones metabolism, Intracellular Signaling Peptides and Proteins physiology, Stem Cells metabolism
- 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/beta-catenin signaling on progenitor cell regulation and cell cycle gene expression, and loss of epithelial Pygo2 completely rescues beta-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/beta-catenin target loci, via direct binding to K4-methyl histone H3 and recruiting histone H3 K4 methyltransferase complexes.
- Published
- 2009
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