EZHIP boosts neuronal-like synaptic gene programs and depresses polyamine metabolism in human neural models

EZHIP (Enhancer of Zeste Inhibitory Protein) is an enigmatic protein with no discernible domains, primarily known for its role in inhibiting PRC2-mediated H3K27 methylation. It is highly expressed in posterior fossa type A (PFA) ependymoma, where it drives global chromatin reorganization. Using human neural models, we show that EZHIP activates neuronal-like transcriptional programs while repressing genes involved in metabolic regulation. Metabolomic analyses indicate that EZHIP suppresses methionine and polyamine metabolism, potentially contributing to the histone and DNA methylation alterations observed in PFA. These findings highlight a metabolic dimension to EZHIP's function and suggest that targeting polyamine metabolism may represent a therapeutic avenue for PFA. Overall design: RNA-seq analysis of human neural progenitor cell (hNPC) models and their derivatives with EZHIP overexpression.