Ezh2 Delays Activation of Differentiation Genes During Normal Cerebellar Granule Neuron Development and in Medulloblastoma
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eLife Assessment
Using an unbiased approach, this important study discovered a role of Ezh2 in the differentiation of granule neuron precursors, the cell of origin for Shh group of medulloblastoma. Furthermore, the authors also provided solid evidence that combined inhibition of Ezh2 and CDK4/6 likely represents a promising strategy for the treatment of this subgroup of MB. Validation of these findings using the FDA-approved Ezh2 inhibitor is needed to further strengthen this preclinical study.
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Abstract
Medulloblastoma (MB) is the most common malignant brain tumour in children. The Sonic Hedgehog (SHH)-medulloblastoma subtype arises from the cerebellar granule neuron lineage. Terminally differentiated neurons are incapable of undergoing further cell division, so an effective treatment for this tumour could be to force neuronal differentiation. Differentiation therapy provides a potential alternative for patients with medulloblastoma who harbor mutations that impair cell death pathways (TP53), which is associated a with high mortality. To this end, our goal was to explore epigenetic regulation of cerebellar granule neuron differentiation in medulloblastoma cells. Key regulators were discovered using chromatin immunoprecipitation with high-throughput sequencing. DNA-bound protein and chromatin protein modifications were investigated across all genes. We discovered that Ezh2-mediated tri-methylation of the H3 histone (H3K27me3), occurred on more than half of the 787 genes whose transcription normally increases as granule neurons terminally differentiate. Conditional knockout of Ezh2 led to early initiation of differentiation in granule neuron precursors (GNPs), but only after cell cycle exit had occurred. Similarly, in MB cells, neuronal differentiation could be induced by preventing H3K27me3 modifications using an Ezh2 inhibitor (UNC1999), but only when UNC1999 was combined with forced cell cycle exit driven by a CDK4/6 inhibitor (Palbociclib). Ezh2 emerges as a powerful restraint upon post-mitotic differentiation during normal GNP development and combination of Ezh2 inhibition with cell cycle exit leads to MB cell differentiation.
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eLife Assessment
Using an unbiased approach, this important study discovered a role of Ezh2 in the differentiation of granule neuron precursors, the cell of origin for Shh group of medulloblastoma. Furthermore, the authors also provided solid evidence that combined inhibition of Ezh2 and CDK4/6 likely represents a promising strategy for the treatment of this subgroup of MB. Validation of these findings using the FDA-approved Ezh2 inhibitor is needed to further strengthen this preclinical study.
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Reviewer #1 (Public review):
In this manuscript, Purzner and colleagues examine the role of Ezh2 in cerebellar development and tumorigenesis using animal models of SHH medulloblastoma (MB). While Ezh2 plays a relatively minor role in granule neuron development and SHH MB, the authors demonstrate that Ezh2 inhibition, when combined with enforced cell cycle exit, promotes MB cell differentiation and potentially reduces malignancy. Overall, this study is solid and provides valuable insights into Ezh2 regulation in cerebellar development and SHH-MB tumorigenesis.
Strengths:
The authors investigate the role of Ezh2 in granule neuronal differentiation during cerebellar development and medulloblastoma (MB) progression, integrating multi-omics for a comprehensive epigenetic analysis. The use of Ezh2 conditional knockout (cKO) mice and …
Reviewer #1 (Public review):
In this manuscript, Purzner and colleagues examine the role of Ezh2 in cerebellar development and tumorigenesis using animal models of SHH medulloblastoma (MB). While Ezh2 plays a relatively minor role in granule neuron development and SHH MB, the authors demonstrate that Ezh2 inhibition, when combined with enforced cell cycle exit, promotes MB cell differentiation and potentially reduces malignancy. Overall, this study is solid and provides valuable insights into Ezh2 regulation in cerebellar development and SHH-MB tumorigenesis.
Strengths:
The authors investigate the role of Ezh2 in granule neuronal differentiation during cerebellar development and medulloblastoma (MB) progression, integrating multi-omics for a comprehensive epigenetic analysis. The use of Ezh2 conditional knockout (cKO) mice and combination therapy with Ezh2 and CDK4/6 inhibitors shows a promising strategy to induce terminal differentiation in MB cells, with potential therapeutic implications. Additionally, analysis of human SHH-MB samples reveals that higher EZH2 expression correlates with worse survival, indicating the clinical relevance.
Weaknesses:
The study does not fully explore compensatory mechanisms of PRC2 given that the phenotype of Ezh2 conditional knockout (cKO) in GNP development and MB tumor formation is relatively mild.
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Reviewer #2 (Public review):
Summary:
This study used an unbiased approach to evaluate epigenetic dynamics during the differentiation of granule neuron precursors, the cell of origin for Shh-MB. These profiling findings led to the focus on H3K27me3 dynamics, which correlate with the remodeling of epigenetic landscape associated with neuronal differentiation gene activation.
Strengths:
Depletion of EZH2, an enzymatic subunit of PRC2, resulted in premature neuronal differentiation in the developing cerebellum.
Weaknesses:
Little information is shown about the specific genetic programs disrupted by EZH2 depletion. This is a crucial weakness as existing PRC2 inhibitors do not effectively cross the blood-brain barrier. Further studies are necessary to identify downstream targets of PRC2 that could be targeted to induce neuronal …
Reviewer #2 (Public review):
Summary:
This study used an unbiased approach to evaluate epigenetic dynamics during the differentiation of granule neuron precursors, the cell of origin for Shh-MB. These profiling findings led to the focus on H3K27me3 dynamics, which correlate with the remodeling of epigenetic landscape associated with neuronal differentiation gene activation.
Strengths:
Depletion of EZH2, an enzymatic subunit of PRC2, resulted in premature neuronal differentiation in the developing cerebellum.
Weaknesses:
Little information is shown about the specific genetic programs disrupted by EZH2 depletion. This is a crucial weakness as existing PRC2 inhibitors do not effectively cross the blood-brain barrier. Further studies are necessary to identify downstream targets of PRC2 that could be targeted to induce neuronal differentiation in MB cells.
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