Thyroid cancer-associated EZH1 Q571R mutation drives chromatin compaction and H3K27me3 invasion into active chromatin.

Dysregulation of Polycomb Repressive Complex 2 (PRC2) contributes to cancer. Of its catalytic subunits, Enhancer of Zeste (EZH) 1 and EZH2, EZH2 mutations are extensively studied, but the role of EZH1 in cancer remains largely unexplored. Here, we investigate the thyroid cancer-associated EZH1Q571R mutation and uncover a mechanism that extends beyond catalytic gain of function. Using biochemical, single-molecule, epigenomic, and transcriptomic analyses, we demonstrated that EZH1Q571R significantly enhances chromatin compaction and stimulates PRC2-EZH1 catalytic activity, thereby rewiring PRC2-chromatin interactions. This altered engagement enables PRC2 activity within H3K36me2-marked chromatin typically refractory to H3K27 methylation, leading to widespread epigenetic and transcriptional reprogramming. Notably, enhanced chromatin compaction is observed with EZH1Q571R but not with the corresponding EZH2Q570R mutation, indicating an EZH1-specific mechanism. Functionally, EZH1Q571R accelerated tumor growth in vivo and induced pronounced micronuclei formation ex vivo, reflecting aberrant chromatin compaction and genome instability. Together, our study demonstrates that EZH1Q571R promotes a permissive epigenomic landscape for the progression of follicular thyroid cancer.