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: CATACOMB (catalytic antagonist of Polycomb; official gene name: EZHIP). We map CATACOMB’s 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 CATACOMB expression is regulated through DNA methylation/ demethylation, we propose CATACOMB 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.
Original language | English (US) |
---|---|
Article number | eaax2887 |
Journal | Science Advances |
Volume | 5 |
Issue number | 7 |
DOIs | |
State | Published - 2019 |
Funding
We thank all the members of Shilatifard’s laboratory for the very fruitful discussions, important inputs, and comments. We thank M. Dyson for crucial advice on primary endometrial stromal cell derivation and growth, S. Y. Kim for technical support, and B. Cenik for suggesting the name CATACOMB. We thank D. Pasini for sharing several plasmids. This work was supported by grants from the NIH, R00DC013805 to J.N.S., K08HL128867 to B.D.S., R50CA211428 to E.R.S., R37-HD38691 to S.E.B., and R35CA197569 to A.S.
ASJC Scopus subject areas
- General