title: Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network.
abstract: Malignant gliomas constitute one of the most significant areas of unmet medical need, owing to the invariable failure of surgical eradication and their marked molecular heterogeneity. Accumulating evidence has revealed a critical contribution by the Polycomb axis of epigenetic repression. However, a coherent understanding of the regulatory networks affected by Polycomb during gliomagenesis is still lacking. Here we integrate transcriptomic and epigenomic analyses to define Polycomb-dependent networks that promote gliomagenesis, validating them both in two independent mouse models and in a large cohort of human samples. We find that Polycomb dysregulation in gliomagenesis affects transcriptional networks associated with invasiveness and de-differentiation. The dissection of these networks uncovers Zfp423 as a critical Polycomb-dependent transcription factor whose silencing negatively impacts survival. The anti-gliomagenic activity of Zfp423 requires interaction with the SMAD proteins within the BMP signalling pathway, pointing to a novel synergic circuit through which Polycomb inhibits BMP signalling.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, via Adamello 16, Milan 20139, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Signaroldi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, via Adamello 16, Milan 20139, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Laise
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, via Adamello 16, Milan 20139, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cristofanon
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, via Adamello 16, Milan 20139, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Brancaccio
authors.affiliation: Trasferimento Genico, IRCCS-AOU San Martino-IST, Largo Rosanna Benzi 10, Genoa 16132, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Reisoli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, via Adamello 16, Milan 20139, Italy.
authors.forename: Sina
authors.identifier: http://orcid.org/0000-0003-0566-5629
authors.initials: S
authors.lastname: Atashpaz
authors.affiliation: Pathology Department, IRCCS San Raffaele Scientific Institute, via Olgettina 60, Milan 20132, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Terreni
authors.affiliation: Pathology Department, IRCCS San Raffaele Scientific Institute, via Olgettina 60, Milan 20132, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.affiliation: Division of Pathology and Laboratory Medicine, European Institute of Oncology, via Ripamonti 435, Milan 20141, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.affiliation: Trasferimento Genico, IRCCS-AOU San Martino-IST, Largo Rosanna Benzi 10, Genoa 16132, Italy.|Department of Experimental Medicine (DiMES), University of Genoa, Via Leon Battista Alberti 2, Genoa 16132, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Malatesta
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, via Adamello 16, Milan 20139, Italy.|Department of Oncology and Hemato-oncology, University of Milan, Via Festa del Perdono 7, Milan 20122, Italy.
authors.forename: Giuseppe
authors.identifier: http://orcid.org/0000-0002-9104-0918
authors.initials: G
authors.lastname: Testa
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing; D005910:Glioma / Q000378:metabolism*; D006657:Histones; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors
chemical_list: D006657:Histones; D063146:Polycomb-Group Proteins; D014157:Transcription Factors