EZH1

Official Full Name

enhancer of zeste 1 polycomb repressive complex 2 subunit

Organism

Homo sapiens

GeneID

2145

Background

EZH1 is a component of a noncanonical Polycomb repressive complex-2 (PRC2) that mediates methylation of histone H3 (see MIM 602812) lys27 (H3K27) and functions in the maintenance of embryonic stem cell pluripotency and plasticity (Shen et al., 2008 [PubMed 19026780]).[supplied by OMIM, Mar 2009]

Synonyms

KMT6B;

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Detailed Information

The Enhancement of Zeste homolog 1 (EZH1) is a novel human gene belonging to the PcG (Ploycomb group) family and a human homolog of the Drosophila zeste gene enhancer. The EZH1 gene is highly conserved during evolution. Three conserved sequences at the N-terminus of EZH1 are highly homologous to the Drosophila (z) gene. These three conserved sequences are Region 1, Region 11, and cysteine-rich regions, respectively. PRC2 (polycomb repressive complex 2) is a complex of multi-subunit proteins consisting of EZH1(enhancer of zeste homologue 1, KMT6B) or EZH2(enhancer of zeste homologue 2, KMT6A), SUZ12(suppressor of zeste 12), and EED(embyronic ectoderm development). EZH1 and EZH2 are homologs of each other, have the same target of the action, and their expressions are complementary in time and space. In the early development of the heart, EZH2 plays a major biological function.

The c-end of EZH1 has a SET domain that is also evolutionarily highly conserved. The source of the SET domain name is because the SET domain was first discovered in su(Var)3-9, Enhancer of zeste, and Trithorax3, so it was named after its initials. The premise that EZH1 plays a physiological role in mediating transcriptional repression is the integrity of the SET domain. If the region is mutated or lost, the inhibitory phenotype cannot be produced, and in some cases, the gene may be de-inhibited.

Since the human PcG gene family is an important gene family, it plays an extremely important role in embryogenesis. At the same time, it is involved in various processes such as cell cycle regulation, x-chromosome inactivation regulation, and hematopoiesis regulation. The PcG gene can form three PcG protein complexes of PRC1, PRC2, and PRC3 by encoding different proteins and complexing them. In the PcG family, EZH1 plays an important role in the formation of PcG protein complexes, playing an important role in embryonic development, mainly in the fetal hematopoietic system as well as the central and peripheral nervous systems. EZH1 is an important component of PRC2, which mainly functions as a histone methyltransferase, which can trimethylation of the ε amino group in the H3K27 side chain. Studies have shown that H3K27 trimethylation is a very important form of PcG silencing. H3K27, which is trimethylated, can reach a specific gene locus by the action of the PRC1 complex, thereby inhibiting genes involved in cell differentiation, cell proliferation, and the like, and finally causing tumors. In addition, EZH1 not only participates in the process of group egg self-methyl transfer, but also plays a very important role in development, reproduction, maintenance of ten cell versatility, x chromosome inactivation, and tumor metastasis and infiltration.

It has been found in some tumors and found to be over-expressed, such as hepatocellular carcinoma, breast cancer, prostate cancer, etc., and has a close relationship with the occurrence and development of tumors and prognosis. Recent studies have shown that the expression of EZH1 may be related to tumor progression and prognosis. The higher the expression of EZH1, the greater the possibility of tumor metastasis and the worse the prognosis.

Further studies have shown that EZH2 mainly regulates the proliferation and differentiation of cardiac precursor cells. EZH1 is mainly responsible for maintaining the proliferation of perinatal infant cardiomyocytes and the proliferation and regeneration of cardiomyocytes after adult myocardial infarction. EZH1 and EZH2 have a certain overlapping effect on the proliferation and differentiation of cardiomyocytes and the regulation of cardiomyocyte maturation in late embryonic development. Garapatyrao et al. screened highly selective EZH1/2 inhibitors, and studies have shown that these inhibitors can inhibit the methylation of histone H3-lys27, affecting gene expression, leading to selective proliferation defects.

EZH1 Figure 1.The role of EZH1/2 inhibitor (Garapatyrao, et al. 2013)

Zhu et al. found that miR-214-3p (microRNA-214-3p) inhibits cardiac gene expression in fibroblasts by directly targeting EZH1/2. miR-214-3p binds to the EZH1/2 enhancer 3'-UTRs and inhibits EZH1/2 expression at the transcriptional level. Furthermore, the expression of peroxisome proliferator-activated receptor (PPAR-γ) in cardiac fibroblasts is enhanced, and the expression of type I collagen genes Col1a1 and Col3a1 is decreased, which ultimately slows down angiotensin II-induced collagen deposition in mouse myocardial tissue and myocardial fibrosis. However, overexpression of miR-214 can lead to cardiac hypertrophy and cardiac dysfunction, in part because of a reduced EZH2 transcript level.

References:

Ai, S., Yu, X., Li, Y., Peng, Y., Li, C., & Yue, Y., et al. (2017). Divergent requirements for ezh1 in heart development versus regeneration. Circulation Research, 121(2), 106-112.
Garapatyrao, S., Nasveschuk, C., Gagnon, A., Chan, E. Y., Sandy, P., & Busby, J., et al. (2013). Identification of ezh2 and ezh1 small molecule inhibitors with selective impact on diffuse large b cell lymphoma cell growth. Chemistry & Biology, 20(11), 1329-1339.
Zhu, W. S., Tang, C. M., Xiao, Z., Zhu, J. N., Lin, Q. X., & Fu, Y. H., et al. (2016). Targeting ezh1 and ezh2 contributes to the suppression of fibrosis-associated genes by mir-214-3p in cardiac myofibroblasts. Oncotarget, 7(48), 78331-78342.
Kook, H., Seo, S. B., & Jain, R. (2017). Ez switch from ezh2 to ezh1: histone methylation opens a window of cardiac regeneration. Circulation Research, 121(2), 91.

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