Plant-specific transcriptional regulators called TELOMERE REPEAT BINDING proteins(TRBs)combine two DNA-binding domains,the GH1 domain,which binds to linker DNA and is shared with H1 histones,and the Myb/SANT domain,wh...Plant-specific transcriptional regulators called TELOMERE REPEAT BINDING proteins(TRBs)combine two DNA-binding domains,the GH1 domain,which binds to linker DNA and is shared with H1 histones,and the Myb/SANT domain,which specifically recognizes the telobox DNA-binding site motif.TRB1,TRB2,and TRB3 proteins recruit Polycomb group complex 2(PRC2)to deposit H3K27me3 and JMJ14 to remove H3K4me3 at gene promoters containing telobox motifs to repress transcription.Here,we demonstrate that TRB4 and TRB5,two related paralogs belonging to a separate TRB clade conserved in spermatophytes,regulate the transcription of several hundred genes involved in developmental responses to environmental cues.TRB4 binds to several thousand sites in the genome,mainly at transcription start sites and promoter regions of transcriptionally active and H3K4me3-marked genes,but,unlike TRB1,it is not enriched at H3K27me3-marked gene bodies.However,TRB4 can physically interact with the catalytic components of PRC2,SWINGER,and CURLY LEAF(CLF).Unexpectedly,we show that TRB4 and TRB5 are required for distinctive phenotypic traits observed in clf mutant plants and thus function as transcriptional activators of several hundred CLF-controlled genes,including key flowering genes.We further demonstrate that TRB4 shares multiple target genes with TRB1 and physically and genetically interacts with members of both TRB clades.Collectively,these results reveal that TRB proteins engage in both positive and negative interactions with other members of the family to regulate plant development through both PRC2-dependent and-independent mechanisms.展开更多
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
Large-intergenic noncoding RNAs （lincRNAs） cooperate with core transcription factors to coordinate the pluripotency network of embryonic stem cells. The mechanisms by which lincRNAs affect chromatin structure and ge...Large-intergenic noncoding RNAs （lincRNAs） cooperate with core transcription factors to coordinate the pluripotency network of embryonic stem cells. The mechanisms by which lincRNAs affect chromatin structure and gene transcription remain mostly unknown. Here, we identified that a UncRNA （linc1614）, occupied by pluripotency factors at its promoter, was indispensable for both maintenance and acquisition of pluripotency. Linc1614 sewed as a specific partner of core factor Sox2 in maintaining pluripotency, primarily by mediating the function of Sox2 in the repression of developmental genes. Moreover, Ezh2, an essential subunit of polycomb repressive complex 2 （PRC2）, physically interacted with linc1614 and contributed to lincRNA-mediated transcriptional silencing. Thus, we propose that the interplay of linc1614 with Sox2 implicates this lincRNA as a recruitment platform that mediates transcriptional silencing by guiding the PRC2 complex to the loci of developmental genes.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
文摘Plant-specific transcriptional regulators called TELOMERE REPEAT BINDING proteins(TRBs)combine two DNA-binding domains,the GH1 domain,which binds to linker DNA and is shared with H1 histones,and the Myb/SANT domain,which specifically recognizes the telobox DNA-binding site motif.TRB1,TRB2,and TRB3 proteins recruit Polycomb group complex 2(PRC2)to deposit H3K27me3 and JMJ14 to remove H3K4me3 at gene promoters containing telobox motifs to repress transcription.Here,we demonstrate that TRB4 and TRB5,two related paralogs belonging to a separate TRB clade conserved in spermatophytes,regulate the transcription of several hundred genes involved in developmental responses to environmental cues.TRB4 binds to several thousand sites in the genome,mainly at transcription start sites and promoter regions of transcriptionally active and H3K4me3-marked genes,but,unlike TRB1,it is not enriched at H3K27me3-marked gene bodies.However,TRB4 can physically interact with the catalytic components of PRC2,SWINGER,and CURLY LEAF(CLF).Unexpectedly,we show that TRB4 and TRB5 are required for distinctive phenotypic traits observed in clf mutant plants and thus function as transcriptional activators of several hundred CLF-controlled genes,including key flowering genes.We further demonstrate that TRB4 shares multiple target genes with TRB1 and physically and genetically interacts with members of both TRB clades.Collectively,these results reveal that TRB proteins engage in both positive and negative interactions with other members of the family to regulate plant development through both PRC2-dependent and-independent mechanisms.
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.
基金This work was supported by grants from the Ministry of Science and Technology （2016YFA0101300）, the National Natural Science Foundation of China （81530042, 31210103905, 31371510, 31571529, 31571519, 31471250, and 31571390）, the Science and Technology Commission of Shanghai Municipality （15JC1403201）, and the Fundamental Research Funds for the Central Universities （2000219136 and 1500219106）.
文摘Large-intergenic noncoding RNAs （lincRNAs） cooperate with core transcription factors to coordinate the pluripotency network of embryonic stem cells. The mechanisms by which lincRNAs affect chromatin structure and gene transcription remain mostly unknown. Here, we identified that a UncRNA （linc1614）, occupied by pluripotency factors at its promoter, was indispensable for both maintenance and acquisition of pluripotency. Linc1614 sewed as a specific partner of core factor Sox2 in maintaining pluripotency, primarily by mediating the function of Sox2 in the repression of developmental genes. Moreover, Ezh2, an essential subunit of polycomb repressive complex 2 （PRC2）, physically interacted with linc1614 and contributed to lincRNA-mediated transcriptional silencing. Thus, we propose that the interplay of linc1614 with Sox2 implicates this lincRNA as a recruitment platform that mediates transcriptional silencing by guiding the PRC2 complex to the loci of developmental genes.
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。
