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Series GSE131626 Query DataSets for GSE131626
Status Public on Jun 03, 2019
Title CATACOMB: an endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb Repressive complex 2 via a H3K27M-like mechanism
Organism Homo sapiens
Experiment type Methylation profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Summary Dysregulation of Polycomb Repressive Complex 2 (PRC2) function is a common feature of many cancer types, including both solid and hematological malignancies. A number of chromosomal translocations involving Polycomb group proteins have been identified, however, the molecular function of these fusion proteins remains largely unexplored. Here we characterize two endometrial stromal sarcoma (ESS) associated fusion proteins: JAZF1-SUZ12 and MBTD1- CXORF67. We identify JAZF1 as a previously unreported subunit of the NuA4 complex, which when fused to SUZ12 creates a bridge between the NuA4 and PRC2 complexes. Intriguingly, the MBTD1-CXORF67 fusion binds to PRC2 and leads to strongly reduced levels of the PRC2 catalytic products H3K27me2/3. We demonstrate that this inhibitory function is mediated by the CXORF67 half of the fusion protein. Because of this striking property, we propose a new gene name: CATACOMB (CATalytic Antagosnist 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 that of the oncogenic histone H3 lysine-27-to-methionine (H3K27M) mutation found in high grade pediatric gliomas. Finally, we show CATACOMB expression is silenced through DNA methylation and upon treatment with DNA demethylating agents, CATACOMB is expressed, binds to PRC2 and antagonizes its catalytic activity. In conclusion, we have identified an endogenous inducible gene, CATACOMB, that it’s expression can regulate catalytic activity of PRC2 and propose that such mechanism of regulation of histone modifications through the expression of antagonistic subunits may also exist for Trithorax/COMPASS family and other histone modifying enzyme complexes.
Overall design Bisulfite sequencing and RNA-seq in HEK293T and HCT-116 cells treated with5-azacytidine or 5-aza-2-deoxyazacytidine. RNA-seq of U2OS cells treated with EPZ-6438.
Contributor(s) Singer BD, Piunti A, Smith E, Shilatifard A
Citation(s) 31281901
Submission date May 22, 2019
Last update date Jul 16, 2019
Contact name Ali Shilatifard
Organization name Northwestern University Feinberg School of Medicine
Department Department of Biochemistry and Molecular Genetics
Lab Shilatifard Lab
Street address 320 E Superior St
City Chicago
State/province IL
ZIP/Postal code 60611
Country USA
Platforms (2)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (18)
GSM3791391 293T_DMSO
GSM3791392 293T_aza_24hr
GSM3791393 293T_aza_48hr
BioProject PRJNA544242
SRA SRP199200

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Supplementary file Size Download File type/resource
GSE131626_RAW.tar 1.8 Gb (http)(custom) TAR (of BW, COV)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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