title: Uropathogenic E. coli (UPEC) Infection Induces Proliferation through Enhancer of Zeste Homologue 2 (EZH2).
abstract: Host-pathogen interactions can induce epigenetic changes in the host directly, as well as indirectly through secreted factors. Previously, uropathogenic Escherichia coli (UPEC) was shown to increase DNA methyltransferase activity and expression, which was associated with methylation-dependent alterations in the urothelial expression of CDKN2A. Here, we showed that paracrine factors from infected cells alter expression of another epigenetic writer, EZH2, coordinate with proliferation. Urothelial cells were inoculated with UPEC, UPEC derivatives, or vehicle (mock infection) at low moi, washed, then maintained in media with Gentamycin. Urothelial conditioned media (CM) and extracellular vesicles (EV) were isolated after the inoculations and used to treat naïve urothelial cells. EZH2 increased with UPEC infection, inoculation-induced CM, and inoculation-induced EV vs. parallel stimulation derived from mock-inoculated urothelial cells. We found that infection also increased proliferation at one day post-infection, which was blocked by the EZH2 inhibitor UNC1999. Inhibition of demethylation at H3K27me3 had the opposite effect and augmented proliferation.
  
  
  CONCLUSIONS
  Uropathogen-induced paracrine factors act epigenetically by altering expression of EZH2, which plays a key role in early host cell proliferative responses to infection.
authors.affiliation: Faculty of Arts and Sciences, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ting
authors.affiliation: Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.|Urology Division, Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Aitken
authors.affiliation: Urology Division, Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Penna
authors.affiliation: Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Alaleh Najdi
authors.initials: AN
authors.lastname: Samiei
authors.affiliation: Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.|Urology Division, Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Sidler
authors.affiliation: Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jia-Xin
authors.initials: JX
authors.lastname: Jiang
authors.affiliation: Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Fadi
authors.initials: F
authors.lastname: Ibrahim
authors.affiliation: Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Tolg
authors.affiliation: Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.|Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Delgado-Olguin
authors.affiliation: Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.|Nephrology Division, Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Norman
authors.initials: N
authors.lastname: Rosenblum
authors.affiliation: Faculty of Arts and Sciences, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Developmental and Stem Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.|Urology Division, Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Darius J
authors.initials: DJ
authors.lastname: Bägli
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D004927:Escherichia coli Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D019899:Paracrine Communication; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D056689:Uropathogenic Escherichia coli / Q000502:physiology*; D019459:Urothelium / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D006657:Histones; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine