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H3 K27M and EZHIP impede H3K27-methylation spreading by inhibiting allosterically stimulated PRC2.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Drosophila melanogaster

PROVIDER: GSE151983 | GEO | 2020/10/12

REPOSITORIES: GEO

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H3 K27M and EZHIP Impede H3K27-Methylation Spreading by Inhibiting Allosterically Stimulated PRC2.

Project description:Diffuse midline gliomas and posterior fossa type A ependymomas contain the recurrent histone H3 lysine 27 (H3 K27M) mutation and express the H3 K27M-mimic EZHIP (CXorf67), respectively. H3 K27M and EZHIP are competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity. In vivo, these proteins reduce overall H3 lysine 27 trimethylation (H3K27me3) levels; however, residual peaks of H3K27me3 remain at CpG islands (CGIs) through an unknown mechanism. Here, we report that EZHIP and H3 K27M preferentially interact with PRC2 that is allosterically activated by H3K27me3 at CGIs and impede its spreading. Moreover, H3 K27M oncohistones reduce H3K27me3 in trans, independent of their incorporation into the chromatin. Although EZHIP is not found outside placental mammals, expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved mechanism. Our results provide mechanistic insights for the retention of residual H3K27me3 in tumors driven by H3 K27M and EZHIP.

| S-EPMC7680438 | biostudies-literature

H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [EZHIP]

Project description:In this study, we report that EZHIP and H3 K27M preferentially interact with an allosterically activated form of PRC2 in vivo. The formation of H3 K27M- and EZHIP-PRC2 complexes occurs at CpG islands containing H3K27me3 and impedes PRC2 and H3K27me3 spreading. Moreover, we find that H3 K27M inhibits PRC2 in trans and can reduce H3K27me3 levels independent of chromatin incorporation. While EZHIP is not found outside of placental mammals, we find that expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved molecular mechanism.

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H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [K27M]

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H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [nonM]

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H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [S2_ATAC]

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H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [EED_rescue]

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H3 K27M and EZHIP impede H3K27-methylation spreading by inhibing allosterically stimulated PRC2 [S2_H3K27me3]

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H3 K27M and EZHIP impede H3K27-methylation spreading by inhibiting allosterically stimulated PRC2.