Medulloblastoma is the most common malignant childhood brain tumor. The heterogeneous tumors are classified into four subgroups based on transcription profiles. Recent developments in genome-wide sequencing techniques have rapidly advanced the understanding of these tumors. The high percentages of somatic alterations of genes encoding chromatin regulators in all subgroups suggest that epigenetic deregulation is a major driver of medulloblastoma. In this report, we review the current understanding of epigenetic regulation in medulloblastoma with a focus on the functional studies of chromatin regulators in the initiation and progression of specific subgroups of medulloblastoma. We also discuss the potential usage of epigenetic inhibitors for medulloblastoma treatment.

SUMMARY Neuronal activity-induced enhancers drive gene activation. We demonstrate that BRG1, the core subunit of SWI/SNF-like BAF ATP-dependent chromatin remodeling complexes, regulates neuronal activity-induced enhancers. Upon stimulation, BRG1 is recruited to enhancers in an H3K27Ac-dependent manner. BRG1 regulates enhancer basal activities and inducibility by affecting cohesin binding, enhancer-promoter looping, RNA polymerase II recruitment, and enhancer RNA expression. We identify a serine phosphorylation site in BRG1 that is induced by neuronal stimulations and is sensitive to CaMKII inhibition. BRG1 phosphorylation affects its interaction with several transcription co-factors, including the NuRD repressor complex and cohesin, possibly modulating BRG1-mediated transcription outcomes. Using mice with knockin mutations, we show that non-phosphorylatable BRG1 fails to efficiently induce activity-dependent genes, whereas phosphomimic BRG1 increases enhancer activity and inducibility. These mutant mice display anxiety-like phenotypes and altered responses to stress. Therefore, we reveal a mechanism connecting neuronal signaling to enhancer activities through BRG1 phosphorylation.

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SUMMARYNeuronal activity-induced enhancers drive the gene induction in response to stimulation. Here, we demonstrate that BRG1, the core subunit of SWI/SNF-like BAF ATP-dependent chromatin remodeling complexes, regulates neuronal activity-induced enhancers. Upon stimulation, BRG1 is recruited to enhancers in an H3K27Ac-dependent manner. BRG1 regulates enhancer basal activities and inducibility by affecting cohesin binding, enhancer-promoter looping, RNA polymerase II recruitment, and enhancer RNA expression. Furthermore, we identified a serine phosphorylation site in BRG1 that is induced by neuronal activities and is sensitive to CaMKII inhibition. BRG1 phosphorylation affects its interaction with several transcription co-factors, possibly modulating BRG1 mediated transcription outcomes. Using mice with knock-in mutations, we showed that non-phosphorylatable BRG1 fails to efficiently induce activity-dependent genes, whereas phosphomimic BRG1 increases the enhancer activities and inducibility. These mutant mice displayed anxiety-like phenotypes and altered responses to stress. Therefore, our data reveal a mechanism connecting neuronal signaling to enhancer activities through BRG1 phosphorylation.

Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wildtype tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. IGF2 mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones.