TY - JOUR
T1 - Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network
AU - Signaroldi, Elena
AU - Laise, Pasquale
AU - Cristofanon, Silvia
AU - Brancaccio, Arianna
AU - Reisoli, E.
AU - Atashpazgargari, Sina
AU - Terreni, M. R.
AU - Doglioni, Claudio
AU - Pruneri, Giancarlo
AU - Malatesta, Paolo
AU - Testa, Giuseppe
PY - 2016/2/29
Y1 - 2016/2/29
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms10753
DO - 10.1038/ncomms10753
M3 - Article
VL - 7
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 10753
ER -