title: Chromatin effector Pygo2 mediates Wnt-notch crosstalk to suppress luminal/alveolar potential of mammary stem and basal cells.
abstract: Epigenetic mechanisms regulating lineage differentiation of mammary stem cells (MaSCs) remain poorly understood. Pygopus 2 (Pygo2) is a histone methylation reader and a context-dependent Wnt/β-catenin coactivator. Here we provide evidence for Pygo2's function in suppressing luminal/alveolar differentiation of MaSC-enriched basal cells. We show that Pygo2-deficient MaSC/basal cells exhibit partial molecular resemblance to luminal cells, such as elevated Notch signaling and reduced mammary repopulating capability upon transplantation. Inhibition of Notch signaling suppresses basal-level and Pygo2-deficiency-induced luminal/alveolar differentiation of MaSC/basal cells, whereas activation of Wnt/β-catenin signaling suppresses luminal/alveolar differentiation and Notch3 expression in a Pygo2-dependent manner. We show that Notch3 is a direct target of Pygo2 and that Pygo2 is required for β-catenin binding and maintenance of a poised/repressed chromatin state at the Notch3 locus in MaSC/basal cells. Together, our data support a model where Pygo2-mediated chromatin regulation connects Wnt signaling and Notch signaling to restrict the luminal/alveolar differentiation competence of MaSC/basal cells.
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Bingnan
authors.initials: B
authors.lastname: Gu
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Watanabe
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Magid
authors.initials: M
authors.lastname: Fallahi
authors.forename: Xing
authors.initials: X
authors.lastname: Dai
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C499373:Notch3 protein, mouse; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D051153:Wnt Proteins; D051176:beta Catenin; C495570:pygopus 2 protein, mouse