Journal
JOURNAL OF CELL BIOLOGY
Volume 185, Issue 5, Pages 811-826Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200810133
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Funding
- Department of Defense [W81XWH04-1-0516]
- National Institutes of Health [R01-AR47320, K02-AR51482, R01 CA127857, P01 CA30195]
- National Key Research Project of Basic Sciences of China [973 project 2006CB708507]
- National Natural Science Foundation of China [30671173]
- California Breast Cancer Research Program (CBCRP) postdoctoral fellowship [14FB-0129]
- CBCRP award [10-FB-0116]
- Children's Hospital Los Angeles fellowship
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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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