Objective:ATRX is a multifunctional protein that is tightly regulated by and implicated in transcriptional regulation and chromatin remodeling.Numerous studies have shown that genetic alterations in ATRX play a signif...Objective:ATRX is a multifunctional protein that is tightly regulated by and implicated in transcriptional regulation and chromatin remodeling.Numerous studies have shown that genetic alterations in ATRX play a significant role in gliomas.This study aims to further determine the relationship between ATRX and glioma prognosis and identify possible mechanisms for exploring the biological significance of ATRX using large data sets.Methods:We used The Cancer Genome Atlas(TCGA)database and 130 immunohistochemical results to confirm the difference in ATRX mutations in high-and low-grade gliomas.An online analysis of the TCGA glioma datasets using the cBioPortal platform was performed to study the relationship between ATRX mutations and IDH1,TP53,CDKN2 A and CDKN2 B mutations in the corresponding TCGA glioma dataset.In combination with clinical pathology data,the biological significance of the relationships were analyzed.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses and annotations of all adjacent genes in the network were performedin the Database for Annotation,Visualization and Integrated Discovery(DAVID)and R language.A protein-protein interaction(PPI)network was constructed,and the interactions of all adjacent nodes were analyzed by the String database and using Cytoscape software.Results:In the selected TCGA glioma datasets,a total of 2,228 patients were queried,21%of whom had ATRX alterations,which co-occurred frequently with TP53 and IDH1 mutations.ATRX alterations are associated with multiple critical molecular events,which results in a significantly improved overall survival(OS)rate.In low-grade gliomas,ATRX mutations are significantly associated with multiple important molecular events,such as ZNF274 and FDXR at mRNA and protein levels.A functional cluster analysis revealed that these genes played a role in chromatin binding and P53,and a link was observed between ATRX and IDH1 and TP53 in the interaction network.ATRX and TP53 are important nodes in the network and have potential links with the blood oxygen imbalance.Conclusions:ATRX mutations have clinical implications for the molecular diagnosis of gliomas and can provide diagnostic and prognostic information for gliomas.ATRX is expected to serve as a new therapeutic target.展开更多
Heterochromatin Protein 1 （HP1） is a major regulator of chromatin structure and function. In animals, the network of proteins interacting with HP1 is mainly associated with constitutive heterochromatin marked by H3K...Heterochromatin Protein 1 （HP1） is a major regulator of chromatin structure and function. In animals, the network of proteins interacting with HP1 is mainly associated with constitutive heterochromatin marked by H3K9me3. HP1 physically interacts with the putative ortholog of the SNF2 chromatin remodeler ATRX, which controls deposition of histone variant H3.3 in mammals. In this study, we show that the Arabidopsis thaliana ortholog of ATRX participates in H3.3 deposition and possesses specific conserved domains in plants. We found that plant Like HP1 （LHP1） protein interacts with ATRX through domains that evolved specifically in land plant ancestors. Loss of ATRX function in Arabidopsis affects the expression of a limited subset of genes controlled by PRC2 （POLYCOMB REPRESSIVE COMPLEX 2）, including the flowering time regulator FLC. The function of ATRX in regulation of flowering time requires novel LHPl-interacting domain and ATPase activity of the ATRX SNF2 helicase domain. Taken together, these results suggest that distinct evolutionary pathways led to the interaction between ATRX and HP1 in mammals and its counterpart LHP1 in plants, resulting in distinct modes of transcriptional regulation.展开更多
目的分析α-地中海贫血/精神发育迟滞综合征X染色体相关基因(ATRX)表达丢失对脑胶质瘤患者预后的影响,同时探究其与胶质瘤分级、胶质瘤分子标志物异柠檬酸脱氢酶(IDH)突变之间的相关性。方法利用计算机检索PubMed、Medline、Web of Scie...目的分析α-地中海贫血/精神发育迟滞综合征X染色体相关基因(ATRX)表达丢失对脑胶质瘤患者预后的影响,同时探究其与胶质瘤分级、胶质瘤分子标志物异柠檬酸脱氢酶(IDH)突变之间的相关性。方法利用计算机检索PubMed、Medline、Web of Science、Ovid、万方医学网、中国知网等数据库,收集自建库至2020年6月国内外发表的关于ARTX表达状态与胶质瘤患者预后及相关指标关系的文献,应用Revman 5.3计算机软件进行Meta分析。结果共纳入文献18篇,4593例患者。其中8篇文献报道了ATRX表达情况与胶质瘤患者总生存期(OS)的关系,结果显示ATRX表达丢失,胶质瘤患者预后更好(HR=0.55,95%CI:0.47~0.64,P<0.001);纳入的5篇文献报道了ATRX的表达情况与胶质瘤患者无病生存期(PFS)的关系,结果显示ATRX丢失,胶质瘤患者PFS显著延长(HR=0.57,95%CI:0.48~0.68,P<0.001);纳入的11篇文献报道了ATRX表达情况与胶质瘤级别的关系,结果显示ATRX表达情况与胶质瘤发生级别显著相关,ATRX丢失更易发生于低级别胶质瘤(OR=2.11,95%CI:1.46~3.05,P<0.001);纳入的7篇文献报道了ATRX表达情况与IDH突变的关系,结果显示ATRX丢失利于IDH突变(OR=13.97,95%CI:10.23~19.08,P<0.001)。结论ATRX丢失提示胶质瘤患者预后更好,其与肿瘤分级、IDH突变具有密切的相关性。展开更多
基金support of the Special Construction Innovation Funded Project for Community in Beijing,Tianjin and Hebei of China(Grant No.18247792D)the Hebei Basic Research Cooperation Project(Grant No.H2018201306)
文摘Objective:ATRX is a multifunctional protein that is tightly regulated by and implicated in transcriptional regulation and chromatin remodeling.Numerous studies have shown that genetic alterations in ATRX play a significant role in gliomas.This study aims to further determine the relationship between ATRX and glioma prognosis and identify possible mechanisms for exploring the biological significance of ATRX using large data sets.Methods:We used The Cancer Genome Atlas(TCGA)database and 130 immunohistochemical results to confirm the difference in ATRX mutations in high-and low-grade gliomas.An online analysis of the TCGA glioma datasets using the cBioPortal platform was performed to study the relationship between ATRX mutations and IDH1,TP53,CDKN2 A and CDKN2 B mutations in the corresponding TCGA glioma dataset.In combination with clinical pathology data,the biological significance of the relationships were analyzed.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses and annotations of all adjacent genes in the network were performedin the Database for Annotation,Visualization and Integrated Discovery(DAVID)and R language.A protein-protein interaction(PPI)network was constructed,and the interactions of all adjacent nodes were analyzed by the String database and using Cytoscape software.Results:In the selected TCGA glioma datasets,a total of 2,228 patients were queried,21%of whom had ATRX alterations,which co-occurred frequently with TP53 and IDH1 mutations.ATRX alterations are associated with multiple critical molecular events,which results in a significantly improved overall survival(OS)rate.In low-grade gliomas,ATRX mutations are significantly associated with multiple important molecular events,such as ZNF274 and FDXR at mRNA and protein levels.A functional cluster analysis revealed that these genes played a role in chromatin binding and P53,and a link was observed between ATRX and IDH1 and TP53 in the interaction network.ATRX and TP53 are important nodes in the network and have potential links with the blood oxygen imbalance.Conclusions:ATRX mutations have clinical implications for the molecular diagnosis of gliomas and can provide diagnostic and prognostic information for gliomas.ATRX is expected to serve as a new therapeutic target.
文摘Heterochromatin Protein 1 （HP1） is a major regulator of chromatin structure and function. In animals, the network of proteins interacting with HP1 is mainly associated with constitutive heterochromatin marked by H3K9me3. HP1 physically interacts with the putative ortholog of the SNF2 chromatin remodeler ATRX, which controls deposition of histone variant H3.3 in mammals. In this study, we show that the Arabidopsis thaliana ortholog of ATRX participates in H3.3 deposition and possesses specific conserved domains in plants. We found that plant Like HP1 （LHP1） protein interacts with ATRX through domains that evolved specifically in land plant ancestors. Loss of ATRX function in Arabidopsis affects the expression of a limited subset of genes controlled by PRC2 （POLYCOMB REPRESSIVE COMPLEX 2）, including the flowering time regulator FLC. The function of ATRX in regulation of flowering time requires novel LHPl-interacting domain and ATPase activity of the ATRX SNF2 helicase domain. Taken together, these results suggest that distinct evolutionary pathways led to the interaction between ATRX and HP1 in mammals and its counterpart LHP1 in plants, resulting in distinct modes of transcriptional regulation.
文摘目的分析α-地中海贫血/精神发育迟滞综合征X染色体相关基因(ATRX)表达丢失对脑胶质瘤患者预后的影响,同时探究其与胶质瘤分级、胶质瘤分子标志物异柠檬酸脱氢酶(IDH)突变之间的相关性。方法利用计算机检索PubMed、Medline、Web of Science、Ovid、万方医学网、中国知网等数据库,收集自建库至2020年6月国内外发表的关于ARTX表达状态与胶质瘤患者预后及相关指标关系的文献,应用Revman 5.3计算机软件进行Meta分析。结果共纳入文献18篇,4593例患者。其中8篇文献报道了ATRX表达情况与胶质瘤患者总生存期(OS)的关系,结果显示ATRX表达丢失,胶质瘤患者预后更好(HR=0.55,95%CI:0.47~0.64,P<0.001);纳入的5篇文献报道了ATRX的表达情况与胶质瘤患者无病生存期(PFS)的关系,结果显示ATRX丢失,胶质瘤患者PFS显著延长(HR=0.57,95%CI:0.48~0.68,P<0.001);纳入的11篇文献报道了ATRX表达情况与胶质瘤级别的关系,结果显示ATRX表达情况与胶质瘤发生级别显著相关,ATRX丢失更易发生于低级别胶质瘤(OR=2.11,95%CI:1.46~3.05,P<0.001);纳入的7篇文献报道了ATRX表达情况与IDH突变的关系,结果显示ATRX丢失利于IDH突变(OR=13.97,95%CI:10.23~19.08,P<0.001)。结论ATRX丢失提示胶质瘤患者预后更好,其与肿瘤分级、IDH突变具有密切的相关性。
