EZHIP, also known as the enhancer of zeste homolog inhibitory protein or CXORF67, is a key regulator involved in the epigenetic modification process. It predominantly functions as a negative regulator of the polycomb repressive complex 2 (PRC2), which is responsible for depositing H3K27me2/3 marks, thus playing a crucial role in maintaining transcriptional silencing [2,3,5]. This function of EZHIP is essential in germ cell development and is also associated with various cancers, making it an important gene for understanding both normal biological processes and disease mechanisms [1]. Genetic models, such as knockout (KO) mouse models, can significantly contribute to further elucidating its functions.

In mice, deletion of Ezhip leads to a global increase in H3K27me2/3 deposition during spermatogenesis and late oocyte maturation [2]. This finding suggests that EZHIP is a key regulator of the chromatin landscape in gametes. In diseases, aberrant expression of EZHIP is observed in 4% of diffuse midline gliomas (DMGs), mirroring the H3 K27M oncohistone mutation hallmark of DMGs [1]. Similar to H3 K27M, EZHIP leads to global epigenomic remodeling by inhibiting PRC2 [1]. In posterior fossa type A (PFA) ependymomas, EZHIP overexpression causes a global reduction of H3K27me3, similar to the oncohistone H3K27M [6]. Additionally, EZHIP expression induces the formation of type B ultra long-range interactions in PFAs (TULIPs), a characteristic feature of PFA ependymomas [4].

In conclusion, EZHIP is a crucial regulator of the chromatin landscape, especially in germ cells. Through its inhibition of PRC2, it influences epigenetic modification. Model-based research, particularly Ezhip KO mouse models, has revealed its role in gamete development and in diseases such as DMGs and PFA ependymomas. Understanding EZHIP provides insights into both normal biological processes and potential therapeutic targets for associated diseases.

References:

1. Cassim, Afraah, Dun, Matthew D, Gallego-Ortega, David, Valdes-Mora, Fatima. 2024. EZHIP's role in diffuse midline glioma: echoes of oncohistones? In Trends in cancer, 10, 1095-1105. doi:10.1016/j.trecan.2024.09.002. https://pubmed.ncbi.nlm.nih.gov/39343635/

2. Ragazzini, Roberta, Pérez-Palacios, Raquel, Baymaz, Irem H, Vermeulen, Michiel, Margueron, Raphaël. 2019. EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells. In Nature communications, 10, 3858. doi:10.1038/s41467-019-11800-x. https://pubmed.ncbi.nlm.nih.gov/31451685/

3. Jain, Siddhant U, Rashoff, Andrew Q, Krabbenhoft, Samuel D, Harrison, Melissa M, Lewis, Peter W. 2020. H3 K27M and EZHIP Impede H3K27-Methylation Spreading by Inhibiting Allosterically Stimulated PRC2. In Molecular cell, 80, 726-735.e7. doi:10.1016/j.molcel.2020.09.028. https://pubmed.ncbi.nlm.nih.gov/33049227/

4. Johnston, Michael J, Lee, John J Y, Hu, Bo, Taylor, Michael D, Gallo, Marco. 2024. TULIPs decorate the three-dimensional genome of PFA ependymoma. In Cell, 187, 4926-4945.e22. doi:10.1016/j.cell.2024.06.023. https://pubmed.ncbi.nlm.nih.gov/38986619/

5. Jain, Siddhant U, Do, Truman J, Lund, Peder J, Jabado, Nada, Lewis, Peter W. 2019. PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. In Nature communications, 10, 2146. doi:10.1038/s41467-019-09981-6. https://pubmed.ncbi.nlm.nih.gov/31086175/

6. Panwalkar, Pooja, Tamrazi, Benita, Dang, Derek, Judkins, Alexander R, Venneti, Sriram. 2021. Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas. In Science translational medicine, 13, eabc0497. doi:10.1126/scitranslmed.abc0497. https://pubmed.ncbi.nlm.nih.gov/34613815/