The cell proliferation antigen Ki-67 organises heterochromatin

Michal Sobecki (1) , Karim Mrouj (1) , Alain Camasses (1) , Nikolaos Parisis (1) , Emilien Nicolas (2) , David Llères (1) , François Gerbe (3) , Susana Prieto (1) , Liliana Krasinska (1) , Alexandre David (3) , Manuel Eguren (4) , Marie-Christine Birling (5) , Serge Urbach (3) , Sonia Hem (6) , Jérôme Déjardin (7) , Marcos Malumbres (4) , Philippe Jay (3) , Vjekoslav Dulic (1) , Denis Lafontaine (2) , Robert Feil (1) , Daniel Fisher (1)

1 IGMM - Institut de Génétique Moléculaire de Montpellier
2 IBMM - CMMI - Center for Microscopy and Molecular Imaging
3 IGF - Institut de Génomique Fonctionnelle
4 CNIO - Spanish National Cancer Research Center
5 ICS - Institut Clinique de la Souris
6 MSPP - Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform
7 IGH - Institut de génétique humaine

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.

Mots clés: cell biology; antigen; regulator; heterochromatin; cell proliferation; human; gene expression; mouse; Ki-67

Mots clés: antigène; cellule mammaire; expression génique; régulateur

Domaines: Biologie moléculaire; Réseaux moléculaires [q-bio.MN]; Organisation et fonctions cellulaires [q-bio.SC]

Michal Sobecki, Karim Mrouj, Alain Camasses, Nikolaos Parisis, Emilien Nicolas, et al.. The cell proliferation antigen Ki-67 organises heterochromatin. eLife, 2016, 5, pp.e13722. ⟨10.7554/eLife.13722⟩. ⟨hal-02120902⟩