Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network

Elena Signaroldi, Pasquale Laise, Silvia Cristofanon, Arianna Brancaccio, Elisa Reisoli, Sina Atashpaz, Maria Rosa Terreni, Claudio Doglioni, Giancarlo Pruneri, Paolo Malatesta and Giuseppe Testa ()
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Elena Signaroldi: European Institute of Oncology
Pasquale Laise: European Institute of Oncology
Silvia Cristofanon: European Institute of Oncology
Arianna Brancaccio: European Institute of Oncology
Elisa Reisoli: Trasferimento Genico, IRCCS-AOU San Martino-IST
Sina Atashpaz: European Institute of Oncology
Maria Rosa Terreni: IRCCS San Raffaele Scientific Institute
Claudio Doglioni: IRCCS San Raffaele Scientific Institute
Giancarlo Pruneri: European Institute of Oncology
Paolo Malatesta: Trasferimento Genico, IRCCS-AOU San Martino-IST
Giuseppe Testa: European Institute of Oncology

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10753

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