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. [10.1038/ncomms10753]

Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network

E. Signaroldi;G. Pruneri;G. Testa
2016-02

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.
growth-factor receptor; cancer stem-cells; breast-cancer; cerebellar development; human glioblastoma; neural precursors; initiaging cells; proteins bind; mouse model; EZH2
Settore BIO/11 - Biologia Molecolare
Settore BIO/13 - Biologia Applicata
Settore BIO/18 - Genetica
Settore MED/04 - Patologia Generale
Settore BIO/10 - Biochimica
NATURE COMMUNICATIONS
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/374281
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