title: MAP3K4/CBP-regulated H2B acetylation controls epithelial-mesenchymal transition in trophoblast stem cells.
abstract: Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histones H2A and H2B by CBP is required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4-deficient TS cells defines an H2B acetylation-regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveals previously unrecognized genes potentially contributing to breast cancer.
authors.affiliation: Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA. amy_abell@med.unc.edu
authors.forename: Amy N
authors.initials: AN
authors.lastname: Abell
authors.forename: Nicole Vincent
authors.initials: NV
authors.lastname: Jordan
authors.forename: Weichun
authors.initials: W
authors.lastname: Huang
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Midland
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Johnson
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Granger
authors.forename: Piotr A
authors.initials: PA
authors.lastname: Mieczkowski
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gomez
authors.forename: Leping
authors.initials: L
authors.lastname: Li
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D048768:MAP Kinase Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D039902:Multipotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism*; D014327:Trophoblasts / Q000473:pathology
chemical_list: D006657:Histones; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D048768:MAP Kinase Kinase Kinase 4