Weaver syndrome (WS) is a developmental overgrowth and intellectual disability disorder caused by heterozygous mutations in EZH2. EZH2 encodes the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2) which mediates methylation of histone H3 lysine residue 27 (H3K27). Although PRC2 has been extensively studied at the molecular level, the effects of WS-associated EZH2 mutations on cells remain poorly understood. In this study, we expressed WS-associated EZH2 variants in mouse embryonic stem cells and found that they have dominant negative effects on Polycomb repressive function. These EZH2 variants decrease H3K27me2/3 and increase H3K27ac levels at intergenic regions, causing global chromatin decompaction and transcriptional upregulation of sensitive Polycomb target genes. Interestingly, a contrasting EZH2 variant linked to growth restriction caused opposing changes in H3K27 methylation and acetylation, and repressed the same cohort of Polycomb target genes. Our study provides insights into the molecular mechanisms of EZH2-mutant human growth disorders, revealing the opposing changes in chromatin and transcription associated with Weaver syndrome and growth restriction, respectively.

Dominant negative and directional dysregulation of Polycomb function inEZH2-mutant human growth disorders