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Published online
doi:10.1083/jcb.200810133
The Journal of Cell Biology, Vol. 185, No. 5, 811-826
The Rockefeller University Press, 0021-9525 $30.00
© Gu et al.
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Article

Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation



Bingnan Gu1, Peng Sun1, Yuanyang Yuan1,4,5, Ricardo C. Moraes6,7, Aihua Li1, Andy Teng1, Anshu Agrawal3, Catherine Rhéaume1, Virginia Bilanchone1, Jacqueline M. Veltmaat8, Ken-Ichi Takemaru9, Sarah Millar10,11, Eva Y.-H.P. Lee1, Michael T. Lewis6,7, Boan Li1,4,5, and Xing Dai1,2

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.

B. Gu and P. Sun contributed equally to this paper.

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.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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