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.
Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network / E. Signaroldi, P. Laise, S. Cristofanon, A. Brancaccio, E. Reisoli, S. Atashpaz, M.R. Terreni, C. Doglioni, G. Pruneri, P. Malatesta, G. Testa. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 7(2016 Feb), pp. 10753.1-10753.14.
|Titolo:||Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network|
SIGNAROLDI, ELENA (Primo)
TESTA, GIUSEPPE (Corresponding)
|Parole Chiave:||growth-factor receptor; cancer stem-cells; breast-cancer; cerebellar development; human glioblastoma; neural precursors; initiaging cells; proteins bind; mouse model; EZH2|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
Settore BIO/13 - Biologia Applicata
Settore BIO/18 - Genetica
Settore MED/04 - Patologia Generale
Settore BIO/10 - Biochimica
|Data di pubblicazione:||feb-2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/ncomms10753|
|Appare nelle tipologie:||01 - Articolo su periodico|