title: The cell proliferation antigen Ki-67 organises heterochromatin.
abstract: Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not prevent cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 was relocalised within the nucleus. Finally, overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression.
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: Michal
authors.initials: M
authors.lastname: Sobecki
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Mrouj
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Camasses
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: Nikolaos
authors.identifier: http://orcid.org/0000-0002-5706-0122
authors.initials: N
authors.lastname: Parisis
authors.affiliation: RNA Molecular Biology, Center for Microscopy and Molecular Imaging, Fonds de la Recherche Nationale, Université Libre de Bruxelles, Charleroi-Gosselies, Belgium.
authors.forename: Emilien
authors.initials: E
authors.lastname: Nicolas
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Llères
authors.affiliation: Faculty of Sciences, University of Montpellier, Montpellier, France.|Institute of Functional Genomics (IGF), CNRS UMR 5203, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|U1191, Inserm, Montpellier, France.
authors.forename: François
authors.initials: F
authors.lastname: Gerbe
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: Susana
authors.initials: S
authors.lastname: Prieto
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: Liliana
authors.initials: L
authors.lastname: Krasinska
authors.affiliation: Faculty of Sciences, University of Montpellier, Montpellier, France.|Institute of Functional Genomics (IGF), CNRS UMR 5203, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|U1191, Inserm, Montpellier, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: David
authors.affiliation: Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Manuel
authors.identifier: http://orcid.org/0000-0003-0850-939X
authors.initials: M
authors.lastname: Eguren
authors.affiliation: ICS, Mouse Clinical Institute, Illkirch-Graffenstaden, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Birling
authors.affiliation: Faculty of Sciences, University of Montpellier, Montpellier, France.|Institute of Functional Genomics (IGF), CNRS UMR 5203, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|U1191, Inserm, Montpellier, France.|Functional Proteomics Platform, Institute of Functional Genomics, Montpellier, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Urbach
authors.affiliation: Mass Spectrometry Platform MSPP, SupAgro, Montpellier, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Hem
authors.affiliation: Faculty of Sciences, University of Montpellier, Montpellier, France.|Institute of Human Genetics (IGH) CNRS UPR 1142, Centre National de la Recherche Scientifique, Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Déjardin
authors.affiliation: Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Marcos
authors.identifier: http://orcid.org/0000-0002-0829-6315
authors.initials: M
authors.lastname: Malumbres
authors.affiliation: Faculty of Sciences, University of Montpellier, Montpellier, France.|Institute of Functional Genomics (IGF), CNRS UMR 5203, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|U1191, Inserm, Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jay
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: Vjekoslav
authors.initials: V
authors.lastname: Dulic
authors.affiliation: RNA Molecular Biology, Center for Microscopy and Molecular Imaging, Fonds de la Recherche Nationale, Université Libre de Bruxelles, Charleroi-Gosselies, Belgium.
authors.forename: Denis Lj
authors.initials: DLj
authors.lastname: Lafontaine
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: Robert
authors.identifier: http://orcid.org/0000-0002-5671-5860
authors.initials: R
authors.lastname: Feil
authors.affiliation: Montpellier Institute of Molecular Genetics (IGMM) CNRS UMR 5535, Centre National de la Recherche Scientifique (CNRS), Montpellier, France.|Faculty of Sciences, University of Montpellier, Montpellier, France.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-0822-3482
authors.initials: D
authors.lastname: Fisher
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006570:Heterochromatin / Q000378:metabolism* / Q000648:ultrastructure*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D051379:Mice; D014981:Xenopus
chemical_list: D006570:Heterochromatin; D019394:Ki-67 Antigen
keywords: Ki-67; cell biology; cell proliferation; heterochromatin; human; mouse