Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network [ChIP-Seq]. Mus musculus

Malignant gliomas constitute one of the most significant areas of unmet medical need, due 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 found that Polycomb dysregulation in gliomagenesis affects transcriptional networks associated to invasiveness and de-differentiation. The dissection of these networks uncovers Zfp423 as a crtitical Polycomb-dependent transcription factor whose silencing negatively impacts survival. The anti-gliomagenic activity of Zfp423 requires interaction with the SMAD proteins within the BMP signaling pathway, pointing to a novel synergic circuit through which Polycomb inhibits BMP signaling. Overall design: Analysis of H3K27me3 distribition in two different stages of gliomagenesis