Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma
NINDS - National Institute of Neurological Disorders and Stroke
About This Grant
Project Summary: PFA ependymoma is a rare and aggressive pediatric brain tumor with a poorly understood molecular mechanism. Unlike many cancers, PFA ependymoma exhibits very few genetic alterations. Instead, it is thought to be driven primarily by epigenetic dysregulation. A key player in this disease is the EZH1/2 inhibitory protein EZHIP, which is normally expressed only in germ cells. EZHIP is aberrantly expressed in PFA ependymoma, where it disrupts the function of Polycomb Repressive Complex 2 (PRC2), a master epigenetic regulator of developmental gene repression through deposition of the trimethylated histone H3 lysine 27 (H3K27me3) repressive histone mark. EZHIP-mediated dysregulation of PRC2 involves both enzymatic inhibition and physical stalling of PRC2 on CpG island (CGI) chromatin, leading to a global loss of H3K27me3 levels, an epigenetic hallmark of PFA ependymoma. PRC2 itself is a highly dynamic and intricate complex that assembles into two functional variants, PRC2.1 and PRC2.2. These two variants share a core composed of the catalytic subunits EZH1/2, along with EED, SUZ12, and RBBP4/7, and differ by incorporating distinct accessory subunits. PRC2.1 includes PHF1/MTF2/PHF19, EPOP, and PALI1/2, while PRC2.2 features AEBP2 and JARID2. Our preliminary data reveal intriguing molecular crosstalk between EZHIP and multiple PRC2 components, suggesting potential competitive or cooperative interplay. The ability of EZHIP to inhibit PRC2 partly stems from its mimicry of the oncohistone H3K27M, which harbors a lysine-to-methionine mutation that causes diffuse midline glioma, another devastating brain tumor in children, where PRC2 activity is also globally suppressed. However, the precise, EZHIP-specific mechanisms behind PRC2 dysregulation in PFA ependymoma remain largely unexplored. Our work aims to uncover these elusive mechanisms using a powerful combination of structural biology, biochemistry, and genomics approaches. Ultimately, we aim to identify therapeutic strategies that disrupt the pathogenic EZHIP–PRC2 crosstalk and restore the normal H3K27me3 epigenetic landscape. Specifically, in Aim 1, we will determine the structural and biochemical mechanisms underlying the enzymatic inhibition of the PRC2 core complex by EZHIP. In Aim 2, we will elucidate the molecular basis of EZHIP-mediated stalling of PRC2 on CGI chromatin, involving PRC2 functional variants. In Aim 3, we will explore an exciting mechanism-based therapeutic strategy to overcome PRC2 enzymatic inhibition and chromatin stalling induced by EZHIP.
Grant Summary
Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma is a NINDS - National Institute of Neurological Disorders and Stroke grant providing up to $384K for university, nonprofit, healthcare org. Applications are due 2031-05-31 (open). Check eligibility and apply with FindGrants.
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Up to $384K
2031-05-31
- 1Confirm your organization is eligible for Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma from NINDS - National Institute of Neurological Disorders and Stroke, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
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Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma: Frequently Asked Questions
Who is eligible for the Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma?
Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma is offered by NINDS - National Institute of Neurological Disorders and Stroke and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma provide?
Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma provides up to $384K per award from NINDS - National Institute of Neurological Disorders and Stroke. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma deadline?
Applications for Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma are due 2031-05-31 (open). Because deadlines can change, verify the date with the funder, NINDS - National Institute of Neurological Disorders and Stroke, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma?
To apply for Targeting the Molecular Crosstalk Between EZHIP and PRC2 in PFA Ependymoma, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NINDS - National Institute of Neurological Disorders and Stroke.