Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation.
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.
Gu
Bingnan
B
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
Sun
Peng
P
Yuan
Yuanyang
Y
Moraes
Ricardo C
RC
Li
Aihua
A
Teng
Andy
A
Agrawal
Anshu
A
Rhéaume
Catherine
C
Bilanchone
Virginia
V
Veltmaat
Jacqueline M
JM
Takemaru
Ken-Ichi
K
Millar
Sarah
S
Lee
Eva Y-H P
EY
Lewis
Michael T
MT
Li
Boan
B
Dai
Xing
X
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
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