title: Menin regulates Inhbb expression through an Akt/Ezh2-mediated H3K27 histone modification.
abstract: Although Men1 is a well-known tumour suppressor gene, little is known about the functions of Menin, the protein it encodes for. Since few years, numerous publications support a major role of Menin in the control of epigenetics gene regulation. While Menin interaction with MLL complex favours transcriptional activation of target genes through H3K4me3 marks, Menin also represses gene expression via mechanisms involving the Polycomb repressing complex (PRC). Interestingly, Ezh2, the PRC-methyltransferase that catalyses H3K27me3 repressive marks and Menin have been shown to co-occupy a large number of promoters. However, lack of binding between Menin and Ezh2 suggests that another member of the PRC complex is mediating this indirect interaction. Having found that ActivinB - a TGFβ superfamily member encoded by the Inhbb gene - is upregulated in insulinoma tumours caused by Men1 invalidation, we hypothesize that Menin could directly participate in the epigenetic-repression of Inhbb gene expression. Using Animal model and cell lines, we report that loss of Menin is directly associated with ActivinB-induced expression both in vivo and in vitro. Our work further reveals that ActivinB expression is mediated through a direct modulation of H3K27me3 marks on the Inhbb locus in Menin-KO cell lines. More importantly, we show that Menin binds on the promoter of Inhbb gene where it favours the recruitment of Ezh2 via an indirect mechanism involving Akt-phosphorylation. Our data suggests therefore that Menin could take an important part to the Ezh2-epigenetic repressive landscape in many cells and tissues through its capacity to modulate Akt phosphorylation.
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Samuele
authors.initials: S
authors.lastname: Gherardi
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Doriane
authors.initials: D
authors.lastname: Ripoche
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Mikaelian
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Chanal
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Teinturier
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Goehrig
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Cordier-Bussat
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Chang X
authors.initials: CX
authors.lastname: Zhang
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Hennino
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Université Lyon 1, Lyon, France. Electronic address: philippe.bertolino@inserm.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertolino
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004622:Embryo, Mammalian / Q000166:cytology; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D056426:Genetic Loci; D006657:Histones / Q000378:metabolism*; D028322:Inhibin-beta Subunits / Q000235:genetics* / Q000378:metabolism; D008239:Lysine; D008745:Methylation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D006657:Histones; C498905:Inhbb protein, mouse; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D028322:Inhibin-beta Subunits; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; D051057:Proto-Oncogene Proteins c-akt; D008239:Lysine
keywords: ActivinB; Akt; Ezh2; H3K27me3; Inhibinbb; Menin