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Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation.

  • Author(s): Gu, Bingnan
  • Sun, Peng
  • Yuan, Yuanyang
  • Moraes, Ricardo C
  • Li, Aihua
  • Teng, Andy
  • Agrawal, Anshu
  • Rhéaume, Catherine
  • Bilanchone, Virginia
  • Veltmaat, Jacqueline M
  • Takemaru, Ken-Ichi
  • Millar, Sarah
  • Lee, Eva Y-HP
  • Lewis, Michael T
  • Li, Boan
  • Dai, Xing
  • et al.
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.

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