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PMID: 19487454 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation.

The Journal of cell biology ·Vol. 185 ·No. 5 ·2009-06-01 ·Pages 811-26

Gu B, Sun P, Yuan Y, Moraes RC, Li A, Teng A, Agrawal A, Rhéaume C, Bilanchone V, Veltmaat JM, Takemaru K, Millar S, Lee EY, Lewis MT, Li B, Dai X

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.

MeSH Terms
Animals Cell Cycle Cell Proliferation Gene Expression Regulation Histone Methyltransferases Histone-Lysine N-Methyltransferase Histones/metabolism Humans Intracellular Signaling Peptides and Proteins/metabolism,physiology Lysine/metabolism Mammary Glands, Animal/cytology,growth & development,metabolism Methylation Mice Phenotype Stem Cells/metabolism Wnt Proteins/genetics,metabolism beta Catenin/genetics,metabolism
Chemicals
Histones Intracellular Signaling Peptides and Proteins PYGO2 protein, human Wnt Proteins beta Catenin pygopus 2 protein, mouse Histone Methyltransferases Histone-Lysine N-Methyltransferase Lysine
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Gu Bingnan
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
Sun Peng
Yuan Yuanyang
Moraes Ricardo C
Li Aihua
Teng Andy
Agrawal Anshu
Rhéaume Catherine
Bilanchone Virginia
Veltmaat Jacqueline M
Takemaru Ken-Ichi
Millar Sarah
Lee Eva Y-H P
Lewis Michael T
Li Boan
Dai Xing
References (86)
86 references, click to expand
  1. Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex.
    Nat Cell Biol. 2008 Jan;10(1):77-84 PMID: 18066051
  2. The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes.
    Genes Dev. 2006 Mar 1;20(5):586-600 PMID: 16510874
  3. p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity.
    Genes Dev. 2005 Mar 15;19(6):756-67 PMID: 15769947
  4. Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2.
    Nature. 2006 Jul 6;442(7098):100-3 PMID: 16728977
  5. Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis.
    Mol Cell Biol. 2000 Nov;20(22):8602-12 PMID: 11046155
  6. Identification of Stem Cell Units in the Terminal End Bud and Duct of the Mouse Mammary Gland.
    J Biomed Biotechnol. 2001;1(3):133-143 PMID: 12488607
  7. Keratin 6 is not essential for mammary gland development.
    Breast Cancer Res. 2006;8(3):R29 PMID: 16790075
  8. Tamoxifen-stimulated growth of breast cancer due to p21 loss.
    Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):288-93 PMID: 18162533
  9. Developmental phenotypes and reduced Wnt signaling in mice deficient for pygopus 2.
    Genesis. 2007 May;45(5):318-25 PMID: 17458864
  10. Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo.
    Development. 2002 Jan;129(1):53-60 PMID: 11782400
  11. Restricted high level expression of Tcf-4 protein in intestinal and mammary gland epithelium.
    Am J Pathol. 1999 Jan;154(1):29-35 PMID: 9916915
  12. Decoding of methylated histone H3 tail by the Pygo-BCL9 Wnt signaling complex.
    Mol Cell. 2008 May 23;30(4):507-18 PMID: 18498752
  13. Mapping Wnt/beta-catenin signaling during mouse development and in colorectal tumors.
    Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3299-304 PMID: 12626757
  14. Pygopus, a nuclear PHD-finger protein required for Wingless signaling in Drosophila.
    Development. 2002 Jun;129(11):2565-76 PMID: 12015286
  15. Mammary stem cell number as a determinate of breast cancer risk.
    Breast Cancer Res. 2007;9(4):109 PMID: 17688678
  16. Expression of PCNA-binding domain of CtIP, a motif required for CtIP localization at DNA replication foci, causes DNA damage and activation of DNA damage checkpoint.
    Cell Cycle. 2009 May 1;8(9):1409-20 PMID: 19342888
  17. Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium.
    J Cell Biol. 2001 Nov 12;155(4):531-42 PMID: 11706048
  18. Yng1 PHD finger binding to H3 trimethylated at K4 promotes NuA3 HAT activity at K14 of H3 and transcription at a subset of targeted ORFs.
    Mol Cell. 2006 Dec 8;24(5):785-796 PMID: 17157260
  19. Gli3-mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes.
    Development. 2006 Jun;133(12):2325-35 PMID: 16720875
  20. Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer.
    Nat Genet. 2001 May;28(1):53-7 PMID: 11326276
  21. Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature.
    Cancer Cell. 2006 Jul;10(1):13-24 PMID: 16843262
  22. Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control.
    J Biol Chem. 1999 Nov 12;274(46):32931-5 PMID: 10551859
  23. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells.
    Cell. 2002 Oct 18;111(2):241-50 PMID: 12408868
  24. Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal.
    Tissue Cell. 1997 Apr;29(2):239-53 PMID: 9149446
  25. Bmi1 regulates stem cells and proliferation and differentiation of committed cells in mammary epithelium.
    Curr Biol. 2008 Jul 22;18(14):1094-9 PMID: 18635350
  26. Regulation of MLL1 H3K4 methyltransferase activity by its core components.
    Nat Struct Mol Biol. 2006 Aug;13(8):713-9 PMID: 16878130
  27. Molecular and topological characterization of the rat parotid Na+-K+-2Cl- cotransporter1.
    Biochim Biophys Acta. 1998 Aug 14;1373(1):261-9 PMID: 9733980
  28. Wnt-3A/beta-catenin signaling induces transcription from the LEF-1 promoter.
    J Biol Chem. 2002 Sep 6;277(36):33398-410 PMID: 12052822
  29. Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia.
    Development. 2007 Mar;134(6):1231-42 PMID: 17287253
  30. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression.
    Nature. 2006 Jul 6;442(7098):96-9 PMID: 16728974
  31. The Wnt signaling receptor Lrp5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesis.
    J Biol Chem. 2006 Nov 17;281(46):35081-7 PMID: 16973609
  32. p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential.
    Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9089-94 PMID: 10430900
  33. Isolation and characterization of human mammary stem cells.
    Cell Prolif. 2005 Dec;38(6):375-86 PMID: 16300651
  34. Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development.
    Development. 2004 May;131(10):2257-68 PMID: 15102710
  35. Purification and unique properties of mammary epithelial stem cells.
    Nature. 2006 Feb 23;439(7079):993-7 PMID: 16395311
  36. Open conformation chromatin and pluripotency.
    Genes Dev. 2007 Nov 1;21(21):2671-6 PMID: 17974911
  37. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin.
    Cell. 1998 Nov 25;95(5):605-14 PMID: 9845363
  38. A putative human breast stem cell population is enriched for steroid receptor-positive cells.
    Dev Biol. 2005 Jan 15;277(2):443-56 PMID: 15617686
  39. Identification of the mammary line in mouse by Wnt10b expression.
    Dev Dyn. 2004 Feb;229(2):349-56 PMID: 14745960
  40. pygopus Encodes a nuclear protein essential for wingless/Wnt signaling.
    Development. 2002 Sep;129(17):4089-101 PMID: 12163411
  41. Ovol1 regulates meiotic pachytene progression during spermatogenesis by repressing Id2 expression.
    Development. 2005 Mar;132(6):1463-73 PMID: 15716349
  42. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor.
    Nat Med. 2004 Jan;10(1):55-63 PMID: 14702635
  43. Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells.
    Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3789-94 PMID: 9108056
  44. Lef1 is required for the transition of Wnt signaling from mesenchymal to epithelial cells in the mouse embryonic mammary gland.
    Dev Biol. 2006 Jul 1;295(1):219-31 PMID: 16678815
  45. pygopus 2 has a crucial, Wnt pathway-independent function in lens induction.
    Development. 2007 May;134(10):1873-85 PMID: 17428831
  46. Pygo1 and Pygo2 roles in Wnt signaling in mammalian kidney development.
    BMC Biol. 2007 Apr 10;5:15 PMID: 17425782
  47. Histone lysine methylation: a signature for chromatin function.
    Trends Genet. 2003 Nov;19(11):629-39 PMID: 14585615
  48. NFBD1, a novel nuclear protein with signature motifs of FHA and BRCT, and an internal 41-amino acid repeat sequence, is an early participant in DNA damage response.
    J Biol Chem. 2003 Feb 21;278(8):6323-9 PMID: 12475977
  49. Mass spectrometric characterization of the affinity-purified human 26S proteasome complex.
    Biochemistry. 2007 Mar 20;46(11):3553-65 PMID: 17323924
  50. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland.
    Cell. 2006 Dec 1;127(5):1041-55 PMID: 17129787
  51. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
    Nature. 1999 Apr 1;398(6726):422-6 PMID: 10201372
  52. Pygopus residues required for its binding to Legless are critical for transcription and development.
    J Biol Chem. 2004 Feb 13;279(7):5177-83 PMID: 14612447
  53. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex.
    Cell. 2002 Apr 5;109(1):47-60 PMID: 11955446
  54. On mammary stem cells.
    J Cell Sci. 2005 Aug 15;118(Pt 16):3585-94 PMID: 16105882
  55. Separation of the epidermal sheet by dispase.
    Br J Dermatol. 1983 May;108(5):555-60 PMID: 6342649
  56. Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression.
    J Cell Biol. 1994 May;125(3):681-93 PMID: 8175886
  57. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development.
    Cell. 2005 Jun 17;121(6):859-72 PMID: 15960974
  58. Requirement of Pygopus 2 in breast cancer.
    Int J Oncol. 2007 Feb;30(2):357-63 PMID: 17203217
  59. The mouse Ovol2 gene is required for cranial neural tube development.
    Dev Biol. 2006 Mar 1;291(1):38-52 PMID: 16423343
  60. Pygopus and the Wnt signaling pathway: a diverse set of connections.
    Bioessays. 2008 May;30(5):448-56 PMID: 18404694
  61. The development of the terminal end bud in the prepubertal-pubertal mouse mammary gland.
    Anat Rec. 1998 Apr;250(4):459-64 PMID: 9566536
  62. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells.
    Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15853-8 PMID: 14668450
  63. Epigenetic therapy of cancer: past, present and future.
    Nat Rev Drug Discov. 2006 Jan;5(1):37-50 PMID: 16485345
  64. Chibby, a nuclear beta-catenin-associated antagonist of the Wnt/Wingless pathway.
    Nature. 2003 Apr 24;422(6934):905-9 PMID: 12712206
  65. Stem cells and mammary cancer in mice.
    Stem Cell Rev. 2005;1(3):215-23 PMID: 17142858
  66. Inactivation of Chibby affects function of motile airway cilia.
    J Cell Biol. 2009 Apr 20;185(2):225-33 PMID: 19364920
  67. The language of covalent histone modifications.
    Nature. 2000 Jan 6;403(6765):41-5 PMID: 10638745
  68. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes.
    Cancer Cell. 2006 Dec;10(6):515-27 PMID: 17157791
  69. Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation.
    Differentiation. 2003 Jan;71(1):1-17 PMID: 12558599
  70. Loss of p21WAF1/CIP1 accelerates Ras oncogenesis in a transgenic/knockout mammary cancer model.
    Oncogene. 2000 Nov 9;19(47):5338-47 PMID: 11103935
  71. Histone and chromatin cross-talk.
    Curr Opin Cell Biol. 2003 Apr;15(2):172-83 PMID: 12648673
  72. Generation of a functional mammary gland from a single stem cell.
    Nature. 2006 Jan 5;439(7072):84-8 PMID: 16397499
  73. The PHD finger, a nuclear protein-interaction domain.
    Trends Biochem Sci. 2006 Jan;31(1):35-40 PMID: 16297627
  74. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland.
    J Cell Biol. 2007 Jan 1;176(1):19-26 PMID: 17190790
  75. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation.
    Cell Stem Cell. 2009 Jan 9;4(1):80-93 PMID: 19128795
  76. Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium.
    Cell Growth Differ. 1990 Apr;1(4):161-70 PMID: 1707299
  77. Wdr5 is essential for osteoblast differentiation.
    J Biol Chem. 2008 Mar 21;283(12):7361-7 PMID: 18201971
  78. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation.
    Nat Cell Biol. 2007 Feb;9(2):201-9 PMID: 17187062
  79. Identification of c-MYC as a target of the APC pathway.
    Science. 1998 Sep 4;281(5382):1509-12 PMID: 9727977
  80. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice.
    Genes Dev. 1994 Nov 15;8(22):2691-703 PMID: 7958926
  81. The ovo gene required for cuticle formation and oogenesis in flies is involved in hair formation and spermatogenesis in mice.
    Genes Dev. 1998 Nov 1;12(21):3452-63 PMID: 9808631
  82. Signaling pathways in mammary gland development.
    Dev Cell. 2001 Oct;1(4):467-75 PMID: 11703938
  83. Nuclear regulator Pygo2 controls spermiogenesis and histone H3 acetylation.
    Dev Biol. 2008 Aug 15;320(2):446-55 PMID: 18614164
  84. Hematopoietic stem cell quiescence maintained by p21cip1/waf1.
    Science. 2000 Mar 10;287(5459):1804-8 PMID: 10710306
  85. A new nuclear component of the Wnt signalling pathway.
    Nat Cell Biol. 2002 May;4(5):367-73 PMID: 11988739
  86. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling.
    Nature. 2006 Jul 6;442(7098):86-90 PMID: 16728976
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.200810133
Published
2009-06-01
Pages
811-26
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2711593
Subset
IM
Grants
NIAMS NIH HHS · K02 AR051482 · United States
NCI NIH HHS · R01 CA127857 · United States
NIAMS NIH HHS · K02-AR51482 · United States
NCI NIH HHS · P01 CA030195 · United States
NIAMS NIH HHS · R01-AR47320 · United States
NCI NIH HHS · P01 CA30195 · United States
NIAMS NIH HHS · R01 AR047320 · United States
NCI NIH HHS · P30 CA062203 · United States
Corrections
CommentIn
PMID: 19487452
External Links
PubMed source DOI: 10.1083/jcb.200810133 PMC Full Text View journal details
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