CATACOMB: An Endogenous Inducible Gene That Antagonizes H3K27 Methylation Activity of Polycomb Repressive Complex 2 Via an H3K27M-like Mechanism

Using biochemical characterization of fusion proteins associated with endometrial stromal sarcoma, we identified JAZF1 as a new subunit of the NuA4 acetyltransferase complex and CXORF67 as a subunit of the Polycomb Repressive Complex 2 (PRC2). Since CXORF67's interaction with PRC2 leads to decreased PRC2-dependent H3K27me2/3 deposition, we propose a new name for this gene: (catalytic antagonist of Polycomb; official gene name: ). We map inhibitory function to a short highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles the oncogenic histone H3 Lys-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As expression is regulated through DNA methylation/demethylation, we propose as the potential interlocutor between DNA methylation and PRC2 activity. We raise the possibility that similar regulatory mechanisms could exist for other methyltransferase complexes such as Trithorax/COMPASS.