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Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation

¹ Department of Biological Chemistry, ² Developmental Biology Center, and ³ Department of Medicine, University of California, Irvine, Irvine, CA 92697
⁴ Department of Biomedical Sciences and ⁵ Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, Xiamen University, Xiamen, Fujian 361005, People’s Republic of China
⁶ Lester and Sue Smith Breast Center and ⁷ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030
⁸ Institute of Molecular and Cell Biology, A*STAR, Proteos, 138673 Singapore
⁹ Department of Pharmacological Sciences, State University of New York, Stony Brook, Stony Brook, NY 11794
¹⁰ Department of Dermatology and Department of ¹¹ Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Correspondence to Boan Li: bali{at}xmu.edu.cn; or Xing Dai: xdai{at}uci.edu

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.

Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; HMT, histone H3 K4 methyltransferase; MEC, mammary epithelial cell; MMTV, mouse mammary tumor virus; PHD, plant homeo domain; Pygo, Pygopus; SSKO, skin/mammary epithelia–specific knockout; TEB, terminal end bud; Wg, Wingless.

© 2009 Gu et al.
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This article has been cited by other articles:

• Williams, R. (2009). Pygo2 opens chromatin and cycles cells. JCB 185: 756-756 [Full Text]  
• Horsley, V. (2009). Epigenetics, Wnt signaling, and stem cells: the Pygo2 connection. JCB 185: 761-763 [Abstract] [Full Text]  

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