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

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 EZH1 Q571R mutation and uncover a mechanism that extends beyond catalytic gain of function.

Using biochemical, single-molecule, epigenomic, and transcriptomic analyses, we demonstrated that EZH1 Q571R 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.