CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism.

Abstract

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: <i><b>CATACOMB</b></i> (catalytic antagonist of Polycomb; official gene name: <i><b>EZHIP</b></i> ). We map <i><b>CATACOMB's</b></i> 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 Lys²⁷-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. As <i><b>CATACOMB</b></i> expression is regulated through DNA methylation/demethylation, we propose <i><b>CATACOMB</b></i> 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.