Transcriptional repressor REST drives lineage stage–specific chromatin compaction at <i>Ptch1</i> and increases AKT activation in a mouse model of medulloblastoma

Abstract

In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH-α (children 3 to 16 years) and SHH-β (infants) subgroups. Neuronal maturation is greater in SHH-β than SHH-α tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (<i>RESTTG</i> ) wherein conditional <i>NeuroD2</i>-controlled <i>REST</i> transgene expression in lineage-committed <i>Ptch1</i> ^+/- cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context-specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 at <i>Ptch1</i> Expression of <i>Arrb1</i>, which encodes β-arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed <i>RESTTG</i> cells compared with wild-type proliferating CGNPs. Lineage-committed <i>REST^TG</i> cells also had decreased GLI1 activity and increased histone H3K9 methylation at the <i>Ptch1</i> locus, which correlated with premature silencing of <i>Ptch1</i> These cells also had decreased expression of <i>Pten</i>, which encodes a negative regulator of the kinase AKT. Expression of <i>PTCH1</i> and <i>GLI1</i> were less, and <i>ARRB1</i> was somewhat greater, in patient SHH-β than SHH-α MBs, whereas that of <i>PTEN</i> was similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling, <i>PTCH1</i> silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.