EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells

Abstract

The Polycomb machinery is required for the proper orchestration of gene expression by virtue of its critical role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a new cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This alteration of the epigenetic content of mature oocytes does not affect the initial number of follicles but is associated with a reduction of follicles in aging mice. We provide evidences that mature oocytes Ezhip -/-are not fully functional and that fertility is strongly impaired in Ezhip -/-females. Altogether, our study uncovers EZHIP as a novel functional player in the comprehensive chromatin remodeling that occurs in the gonads.

EZHIP is a specific diagnostic biomarker for posterior fossa ependymomas, group PFA and diffuse midline gliomas H3-WT with EZHIP overexpression

“…Our work highlighted the robust specificity of EZHIP staining in all PF ependymomas, group PFA and in all DMG, H3-wildtype with EZHIP overexpression, ruling out the main differential diagnoses encountered in children in the brainstem and in the posterior fossa (Table 1). All germinomas except two exhibited a strong positivity for EZHIP concomitant with a loss of H3K27me3 as published previously [2,7]. Concerning HGG, MYCN-amplified none of our 9 cases (confirmed by DNA-methylation profiling and previously reported [5,6]), were immunopositive, contrarily to a previous study which reported an expression of EZHIP in 13% of cases [1].…”

The interplay between DNA and histone methylation: molecular mechanisms and disease implications

“…Interestingly, oncohistone H3 lysine 27 to methionine (H3K27M) mutation—found in diffuse intrinsic pontine gliomas (DIPGs)—dominantly inhibits PRC2 activity and reduces global H3K27me3 yet results in DNA hypomethylation (Bender et al , 2013; Lewis et al , 2013). Furthermore, EZHIP/CXORF67 , a germline‐specific gene, encodes a protein that binds to and blocks PRC2 spreading from H3K27me3‐occupied CpG islands through an H3K27M‐like mechanism (Jain et al , 2019; Ragazzini et al , 2019). EZHIP is silenced through promoter methylation in adult tissues, and its de‐repression upon DNA hypomethylation results in PRC2 inhibition (Bayliss et al , 2016; Piunti et al , 2019).…”

Nucleosomal Asymmetry Shapes Histone Mark Binding and Promotes Poising at Bivalent Domains

“…Interestingly, asymmetric bivalent nucleosomes displayed preference for PRC2 complexes containing EPOP and EZHIP (Figures 3A and S3A). EPOP and EZHIP have been shown to reduce H3K27me3 levels by competing with binding of PRC2 auxiliary subunits such as JARID2 that confer more potent repressive activity to PRC2 (Beringer et al, 2016; Liefke et al, 2016; Ragazzini et al, 2019) and, in the case of EZHIP, also by directly inhibiting PRC2 activity (Hübner et al, 2019; Jain et al, 2019). The bivalency-specific recruitment of EPOP and EZHIP may therefore further contribute to poising by curbing PRC2 activity.…”