Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that ...Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.展开更多
Zeste基因增强子同源物2(enhancer of Zeste homolog 2,EZH2)是一种重要的甲基转移酶,可作为核心催化亚基与其他成员形成多梳抑制复合物2,并通过调控转录活性进而促进肿瘤细胞的增殖、转移和耐药。EZH2在多种肿瘤组织中过表达或产生功...Zeste基因增强子同源物2(enhancer of Zeste homolog 2,EZH2)是一种重要的甲基转移酶,可作为核心催化亚基与其他成员形成多梳抑制复合物2,并通过调控转录活性进而促进肿瘤细胞的增殖、转移和耐药。EZH2在多种肿瘤组织中过表达或产生功能获得性突变,与肿瘤的发生发展及不良预后密切相关,可作为肿瘤治疗的有效靶点。目前,多种类型的EZH2抑制剂已用于肿瘤的基础和临床治疗研究,并取得里程碑式的成功。本文将对EZH2在肿瘤发生发展中的作用、分子机制和相关抑制剂的研究新进展进行综述。展开更多
多聚梳抑制复合体2作为一种表观遗传调节因子可选择性催化组蛋白H3第27位赖氨酸三甲基化,从而诱导靶基因转录抑制。Zeste基因增强子同源物2(enhancer of zeste homolog 2,EZH2)是多聚梳抑制复合体2中具有酶活性的亚基,在肿瘤触发、进展...多聚梳抑制复合体2作为一种表观遗传调节因子可选择性催化组蛋白H3第27位赖氨酸三甲基化,从而诱导靶基因转录抑制。Zeste基因增强子同源物2(enhancer of zeste homolog 2,EZH2)是多聚梳抑制复合体2中具有酶活性的亚基,在肿瘤触发、进展、转移及耐药性方面有重要作用。EZH2与其他表观遗传修饰酶相互协调介导基因沉默,EZH2超表达是多种实体肿瘤晚期和转移性的标志,EZH2的表达与活性受多种肿瘤相关转录因子的调节,各位点氨基酸残基的磷酸化状态可影响EZH2的催化活性,EZH2基因突变在血液系统恶性肿瘤中频繁发生,除通过经典作用即催化抑癌基因启动子区组蛋白H3第27位赖氨酸甲基化来抑制转录外,EZH2还具有诱导基因活化功能。因此,EZH2成为肿瘤治疗的一个理想靶点,其特异性抑制剂EPZ6438正处于临床Ⅰ/Ⅱ期试验阶段。展开更多
基金financially supported by the National Natural Science Foundation of China,Nos.82172104(to CX),81873767(to HZ)a grant from Jiangsu Provincial Research Hospital,Nos.YJXYY202204(to HZ),YJXYY202204-ZD04(to HZ)+5 种基金a grant from Jiangsu Provincial Key Medical CenterJiangsu Provincial Medical Innovation Center,No.CXZX202212Jiangsu Provincial Medical Key Discipline,No.ZDXK202240the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)Technology Project of Nantong,No.MS22022008(to HZ)Postgraduate Research&Practice Innovation Program of Jiangsu Province,No.SJCX21_1457(to WW)。
文摘Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury.Notably,the gene regulatory network of regenerated myelin differs from that of native myelin.Silencing of enhancer of zeste homolog 2(EZH2)hinders the differentiation,maturation,and myelination of Schwann cells in vitro.To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury,conditional knockout mice lacking Ezh2 in Schwann cells(Ezh2^(fl/fl);Dhh-Cre and Ezh2^(fl/fl);Mpz-Cre)were generated.Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated.This highlights the crucial role of Ezh2 in initiating Schwann cell myelination.Furthermore,we observed that 21 days after inducing a sciatic nerve crush injury in these mice,most axons had remyelinated at the injury site in the control nerve,while Ezh2^(fl/fl);Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates.This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination.In conclusion,EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury.Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.
文摘Zeste基因增强子同源物2(enhancer of Zeste homolog 2,EZH2)是一种重要的甲基转移酶,可作为核心催化亚基与其他成员形成多梳抑制复合物2,并通过调控转录活性进而促进肿瘤细胞的增殖、转移和耐药。EZH2在多种肿瘤组织中过表达或产生功能获得性突变,与肿瘤的发生发展及不良预后密切相关,可作为肿瘤治疗的有效靶点。目前,多种类型的EZH2抑制剂已用于肿瘤的基础和临床治疗研究,并取得里程碑式的成功。本文将对EZH2在肿瘤发生发展中的作用、分子机制和相关抑制剂的研究新进展进行综述。
文摘多聚梳抑制复合体2作为一种表观遗传调节因子可选择性催化组蛋白H3第27位赖氨酸三甲基化,从而诱导靶基因转录抑制。Zeste基因增强子同源物2(enhancer of zeste homolog 2,EZH2)是多聚梳抑制复合体2中具有酶活性的亚基,在肿瘤触发、进展、转移及耐药性方面有重要作用。EZH2与其他表观遗传修饰酶相互协调介导基因沉默,EZH2超表达是多种实体肿瘤晚期和转移性的标志,EZH2的表达与活性受多种肿瘤相关转录因子的调节,各位点氨基酸残基的磷酸化状态可影响EZH2的催化活性,EZH2基因突变在血液系统恶性肿瘤中频繁发生,除通过经典作用即催化抑癌基因启动子区组蛋白H3第27位赖氨酸甲基化来抑制转录外,EZH2还具有诱导基因活化功能。因此,EZH2成为肿瘤治疗的一个理想靶点,其特异性抑制剂EPZ6438正处于临床Ⅰ/Ⅱ期试验阶段。
