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Regulation of Neuronal Maturation through EZH1-Driven H3K27me3 Deposition

Thomas Roule, CHOP Carolina Gracia-Diaz, CHOP Jasmine Akoto, CHOP Naiara Akizu, CHOP

Poster # 25

Mutations in chromatin remodeler genes are frequently detected in neurodevelopmental disorders. The PRC2 complex, mediating gene silencing through H3K27me3 deposition, guides cells into their appropriate lineages during differentiation, including cell differentiation into neurons. Although both EZH1 and EZH2 function as PRC2's methyltransferases for H3K27me3, the higher activity of EZH2 commonly positions it as the primary catalytic subunit of the PRC2 complex. However, while EZH2 expression decreases, EZH1 expression remains stable throughout neuron differentiation, suggesting it plays a key role in regulating H3K27me3 deposition at latter stages of development, notably in maturating or fully differentiated neurons. In agreement, we recently identified patients with two types of EZH1 mutations: gain-of-function (GOF) mutations promoting H3K27me3 activity and neuronal differentiation, and a loss-of-function (LOF) mutation inhibiting these same processes. However, in human pluripotent stem cell derived 8-week neurons, where EZH1 is the likely dominant PRC2 methyltransferase, Western Blot analysis revealed minimal H3K27me3 differences in mutant cells compared to controls. We thus employed Cut&Run and RNAseq to enhance the resolution and identify differentially H3K27me3-regulated genes. Interestingly, both EZH1 mutations disturb H3K27me3 deposition and gene expression, at key neuron-related genes. Altogether, our study strengthens the role of EZH1 in neuronal maturation via regulation of H3K27me3 activity, and identifies genes potentially linked to PRC2-EZH1-driven neurodevelopmental disorders.

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