title: Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation.
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.
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Bingnan
authors.initials: B
authors.lastname: Gu
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Yuanyang
authors.initials: Y
authors.lastname: Yuan
authors.forename: Ricardo C
authors.initials: RC
authors.lastname: Moraes
authors.forename: Aihua
authors.initials: A
authors.lastname: Li
authors.forename: Andy
authors.initials: A
authors.lastname: Teng
authors.forename: Anshu
authors.initials: A
authors.lastname: Agrawal
authors.forename: Catherine
authors.initials: C
authors.lastname: Rhéaume
authors.forename: Virginia
authors.initials: V
authors.lastname: Bilanchone
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Veltmaat
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Takemaru
authors.forename: Sarah
authors.initials: S
authors.lastname: Millar
authors.forename: Eva Y-H P
authors.initials: EY
authors.lastname: Lee
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lewis
authors.forename: Boan
authors.initials: B
authors.lastname: Li
authors.forename: Xing
authors.initials: X
authors.lastname: Dai
mesh_terms: D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D008239:Lysine / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D008745:Methylation; D051379:Mice; D010641:Phenotype; D013234:Stem Cells / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C453401:PYGO2 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; C495570:pygopus 2 protein, mouse; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine