Type 1 diabetes(T1D)is defined by autoimmune-mediated destruction of the insulin-producing pancreatic β-cells.Impaired insulin secretion due to β-cell apoptosis and islet massloss is the main feature of T1D[1].Curre...Type 1 diabetes(T1D)is defined by autoimmune-mediated destruction of the insulin-producing pancreatic β-cells.Impaired insulin secretion due to β-cell apoptosis and islet massloss is the main feature of T1D[1].Current therapeutic strategies for T1D are mainly through subcutaneous administration of insulin or islet/pancreas transplantation.展开更多
印记基因在哺乳动物的生长发育中起重要作用。锌指蛋白331(Zinc Finger Protein 331,ZNF331)基因在人胎盘中被鉴定为母源印记基因,而其在牛中的印记状态还没有被研究。本研究旨在分析ZNF331基因在牛中的印记状态和DNA甲基化的调控机理...印记基因在哺乳动物的生长发育中起重要作用。锌指蛋白331(Zinc Finger Protein 331,ZNF331)基因在人胎盘中被鉴定为母源印记基因,而其在牛中的印记状态还没有被研究。本研究旨在分析ZNF331基因在牛中的印记状态和DNA甲基化的调控机理。首先应用荧光定量RT-PCR方法分析ZNF331基因在牛6个组织及胎盘中的表达,发现ZNF331基因在胎盘中表达量最高,而在肺中表达量较低。应用基于单核苷酸多态性(Single Nucleotide Polymorphism,SNP)的方法分析ZNF331基因在牛组织和胎盘中的等位基因表达状态,发现ZNF331基因在牛组织中为单等位基因表达,而在胎盘中则呈现双等位基因表达。分析位于ZNF331基因启动子区域和内含子1的2个区域的CpG岛甲基化状态,发现2个区域在牛组织和胎盘中均为低甲基化状态,说明被研究区域的甲基化修饰不参与调控ZNF331基因在牛组织中的单等位基因表达。本研究结果为深入研究牛ZNF331基因的功能及印记调控机制奠定了基础。展开更多
Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study...Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study aims to identify potential pathogenetic gene mutations in patients with sporadic KC in the Han Chinese population.Methods:Twenty-five patients with primary KC as well as 50 unrelated population matched healthy controls,were included in this study to identify potential pathogenic gene mutations among sporadic KC patients in the Han Chinese population.Sanger sequencing and whole-exome sequencing(WES)were used to analyze mutations in the zinc finger protein 469(ZNF469)gene.Bioinformatics analysis was conducted to explore the potential role of ZNF469 in KC pathogenesis.Results:Five novel heterozygous missense variants were identified in KC patients.Among them,2 compound heterozygous variants,c.8986G>C(p.E2996Q)with c.11765A>C(p.D3922A),and c.4423C>G(p.L1475V)with c.10633G>A(p.G3545R),were determined to be possible pathogenic factors for KC.Conclusion:Mutations in the ZNF469 gene may contribute to the development of KC in the Han Chinese population.These mutation sites may provide valuable information for future genetic screening of KC patients and their families.展开更多
目的:探讨宿主基因SOX1、JAM3、ZNF671和DLX1的DNA甲基化水平在人乳头瘤病毒(human papillomavirus,HPV)16/18阳性人群中对宫颈上皮内瘤变2级及以上(cervical intraepithelial neoplasia 2 or worse,CIN2+)的诊断价值,构建风险分层模型...目的:探讨宿主基因SOX1、JAM3、ZNF671和DLX1的DNA甲基化水平在人乳头瘤病毒(human papillomavirus,HPV)16/18阳性人群中对宫颈上皮内瘤变2级及以上(cervical intraepithelial neoplasia 2 or worse,CIN2+)的诊断价值,构建风险分层模型,为优化宫颈癌筛查策略提供依据。方法:收集2023年4月—2024年5月在东部战区总医院就诊的HPV16/18阳性女性宫颈脱落细胞样本共141例,采用基于亚硫酸氢盐转化的焦磷酸测序技术检测上述4个基因的DNA甲基化水平。根据组织病理学结果分组,比较DNA甲基化水平在不同病变等级(正常、低级别组织学、高级别组织学、癌症)中的差异。进一步以CIN2+作为阳性结局,通过Logistic回归构建预测模型,评估模型在训练集和测试集中的诊断效能。结果:4个宿主基因的DNA甲基化水平均随病变程度加重而升高,CIN2+组显著高于CIN1-组(P<0.001),均具有较高的诊断特异性。ZNF671在单基因分析中表现最佳,其曲线下面积(area under the curve,AUC)为0.741,联合SOX1构建的模型在训练集与测试集中的AUC分别为0.801和0.745,特异性可达87%,优于任意单一基因。结论:SOX1、JAM3、ZNF671和DLX1的DNA甲基化水平与宫颈病变严重程度密切相关,具有潜在的分流价值。尤其是在HPV16/18阳性人群中,ZNF671表现出良好的CIN2+预测性能,可作为识别癌前病变的辅助决策工具;联合SOX1构建的模型可进一步提高诊断效能。展开更多
The cell fate of primordial germ cell(PGC)in zebrafish is pre-determined by maternally deposited germ plasm,which is packaged into ribonucleoprotein complex in oocytes and inherited into PGC-fated cells in embryos.How...The cell fate of primordial germ cell(PGC)in zebrafish is pre-determined by maternally deposited germ plasm,which is packaged into ribonucleoprotein complex in oocytes and inherited into PGC-fated cells in embryos.However,the maternal factors regulating the assembly of germ plasm and PGC development remain poorly understood.In this study,we report that the maternal transcription factor Znf706 regulates the assembly of germ plasm factors into a granule-like structure localized perinuclearly in PGC during migration.Maternal and zygotic mutants of znf706 exhibit deficient germ plasm scattering at the early embryonic stage,decreased PGC numbers with some mislocation during PGC migration,and a lower female ratio in adulthood.Notably,the implementation of Znf706 CUT&Tag and RNA-seq on immature oocytes uncovers that Znf706 in stage I oocytes may promote transcription of several mitochondrial genes in addition to other functions.Hence,we propose that Znf706 is implicated in germ plasm assembly and PGC development in zebrafish.展开更多
克鲁佩尔相关盒锌指蛋白(KRAB-ZFPs, Krüppel-Associated Box Zinc Finger Proteins)是人类基因组中数量最多的转录因子家族,广泛参与基因表达调控、生长发育及细胞信号通路的调节。锌指蛋白433 (ZNF433, Zinc Finger Protein 433...克鲁佩尔相关盒锌指蛋白(KRAB-ZFPs, Krüppel-Associated Box Zinc Finger Proteins)是人类基因组中数量最多的转录因子家族,广泛参与基因表达调控、生长发育及细胞信号通路的调节。锌指蛋白433 (ZNF433, Zinc Finger Protein 433)基因是KRAB-ZFPs家族的成员,其分子功能和在癌症中的作用尚未被充分研究。在前列腺癌中,ZNF433高表达可促进β-catenin/TCF复合物的形成,激活Wnt/β-catenin信号通路,进而促进癌细胞增殖和迁移,表现为促癌因子。而在肾透明细胞癌中,ZNF433表达下调,其低表达与更高级别的肿瘤分期及较差预后相关,可能与启动子区域的高甲基化导致的转录沉默有关,从而影响肿瘤的发生与进展,表现为抑癌因子。此外,ZNF433的异常表达与癌症患者的临床预后密切相关,提示其在癌症诊断和治疗中的潜在应用价值。本文综述了ZNF433的分子结构、生物学功能及其在前列腺癌和肾透明细胞癌中的作用机制,并探讨了其作为癌症生物标志物和治疗靶点的潜力。未来,进一步解析ZNF433的直接靶基因、上游调控机制及其与肿瘤微环境的相互作用,将有助于深入理解其在癌症中的功能,并为精准治疗提供新的策略。Krüppel-Associated Box Zinc Finger Proteins (KRAB-ZFPs) are the largest family of transcription factors in the human genome, extensively involved in gene expression regulation, development, and modulation of cellular signaling pathways. Zinc Finger Protein 433 (ZNF433) is a member of the KRAB-ZFPs family, but its molecular function and role in cancer have not been fully elucidated. In prostate cancer, ZNF433 overexpression promotes the formation of the β-catenin/TCF complex, activating the Wnt/β-catenin signaling pathway, which subsequently enhances cancer cell proliferation and migration, functioning as an oncogene. In contrast, in clear cell renal cell carcinoma, ZNF433 expression is downregulated, and its low expression is associated with higher tumor grade, advanced stage, and poorer prognosis. This downregulation may be linked to promoter hypermethylation, leading to transcriptional silencing, thereby influencing tumorigenesis and progression, functioning as a tumor suppressor. Moreover, abnormal expression of ZNF433 is closely correlated with clinical prognosis in cancer patients, suggesting its potential application in cancer diagnosis and therapy. This review summarizes the molecular structure, biological functions, and roles of ZNF433 in prostate cancer and ccRCC, while also exploring its potential as a biomarker and therapeutic target for cancer. In the future, further elucidation of ZNF433’s direct target genes, upstream regulatory mechanisms, and interactions with the tumor microenvironment will help deepen our understanding of its role in cancer and provide new strategies for precision therapy.展开更多
基金supported by the National Natural Science Foundation of China(32325024,32400981,32222024,32271224,32471228,and 82270891)the National Key Research and Development Program of China(2023YFA1800400)+3 种基金the Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission(23SG22)the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0507300)the ECNU public platform for Innovation(011)the instruments sharing platform of School of Life Sciences.
文摘Type 1 diabetes(T1D)is defined by autoimmune-mediated destruction of the insulin-producing pancreatic β-cells.Impaired insulin secretion due to β-cell apoptosis and islet massloss is the main feature of T1D[1].Current therapeutic strategies for T1D are mainly through subcutaneous administration of insulin or islet/pancreas transplantation.
基金supported by the National Natural Science Foundation(82271057)the Natural Science Foundation of Hunan Province(2023JJ30818),China。
文摘Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study aims to identify potential pathogenetic gene mutations in patients with sporadic KC in the Han Chinese population.Methods:Twenty-five patients with primary KC as well as 50 unrelated population matched healthy controls,were included in this study to identify potential pathogenic gene mutations among sporadic KC patients in the Han Chinese population.Sanger sequencing and whole-exome sequencing(WES)were used to analyze mutations in the zinc finger protein 469(ZNF469)gene.Bioinformatics analysis was conducted to explore the potential role of ZNF469 in KC pathogenesis.Results:Five novel heterozygous missense variants were identified in KC patients.Among them,2 compound heterozygous variants,c.8986G>C(p.E2996Q)with c.11765A>C(p.D3922A),and c.4423C>G(p.L1475V)with c.10633G>A(p.G3545R),were determined to be possible pathogenic factors for KC.Conclusion:Mutations in the ZNF469 gene may contribute to the development of KC in the Han Chinese population.These mutation sites may provide valuable information for future genetic screening of KC patients and their families.
文摘目的:探讨宿主基因SOX1、JAM3、ZNF671和DLX1的DNA甲基化水平在人乳头瘤病毒(human papillomavirus,HPV)16/18阳性人群中对宫颈上皮内瘤变2级及以上(cervical intraepithelial neoplasia 2 or worse,CIN2+)的诊断价值,构建风险分层模型,为优化宫颈癌筛查策略提供依据。方法:收集2023年4月—2024年5月在东部战区总医院就诊的HPV16/18阳性女性宫颈脱落细胞样本共141例,采用基于亚硫酸氢盐转化的焦磷酸测序技术检测上述4个基因的DNA甲基化水平。根据组织病理学结果分组,比较DNA甲基化水平在不同病变等级(正常、低级别组织学、高级别组织学、癌症)中的差异。进一步以CIN2+作为阳性结局,通过Logistic回归构建预测模型,评估模型在训练集和测试集中的诊断效能。结果:4个宿主基因的DNA甲基化水平均随病变程度加重而升高,CIN2+组显著高于CIN1-组(P<0.001),均具有较高的诊断特异性。ZNF671在单基因分析中表现最佳,其曲线下面积(area under the curve,AUC)为0.741,联合SOX1构建的模型在训练集与测试集中的AUC分别为0.801和0.745,特异性可达87%,优于任意单一基因。结论:SOX1、JAM3、ZNF671和DLX1的DNA甲基化水平与宫颈病变严重程度密切相关,具有潜在的分流价值。尤其是在HPV16/18阳性人群中,ZNF671表现出良好的CIN2+预测性能,可作为识别癌前病变的辅助决策工具;联合SOX1构建的模型可进一步提高诊断效能。
基金supported by the National Natural Science Foundation of China(31988101 to A.M.)the National Key Research and Development Program of China(2023YFA1800300 to X.W.and 2018YFC1003304 to A.M.)the Yunnan Provincial Science and Technology Project at Southwest United Graduate School(202302A0370011 to A.M.).
文摘The cell fate of primordial germ cell(PGC)in zebrafish is pre-determined by maternally deposited germ plasm,which is packaged into ribonucleoprotein complex in oocytes and inherited into PGC-fated cells in embryos.However,the maternal factors regulating the assembly of germ plasm and PGC development remain poorly understood.In this study,we report that the maternal transcription factor Znf706 regulates the assembly of germ plasm factors into a granule-like structure localized perinuclearly in PGC during migration.Maternal and zygotic mutants of znf706 exhibit deficient germ plasm scattering at the early embryonic stage,decreased PGC numbers with some mislocation during PGC migration,and a lower female ratio in adulthood.Notably,the implementation of Znf706 CUT&Tag and RNA-seq on immature oocytes uncovers that Znf706 in stage I oocytes may promote transcription of several mitochondrial genes in addition to other functions.Hence,we propose that Znf706 is implicated in germ plasm assembly and PGC development in zebrafish.
文摘克鲁佩尔相关盒锌指蛋白(KRAB-ZFPs, Krüppel-Associated Box Zinc Finger Proteins)是人类基因组中数量最多的转录因子家族,广泛参与基因表达调控、生长发育及细胞信号通路的调节。锌指蛋白433 (ZNF433, Zinc Finger Protein 433)基因是KRAB-ZFPs家族的成员,其分子功能和在癌症中的作用尚未被充分研究。在前列腺癌中,ZNF433高表达可促进β-catenin/TCF复合物的形成,激活Wnt/β-catenin信号通路,进而促进癌细胞增殖和迁移,表现为促癌因子。而在肾透明细胞癌中,ZNF433表达下调,其低表达与更高级别的肿瘤分期及较差预后相关,可能与启动子区域的高甲基化导致的转录沉默有关,从而影响肿瘤的发生与进展,表现为抑癌因子。此外,ZNF433的异常表达与癌症患者的临床预后密切相关,提示其在癌症诊断和治疗中的潜在应用价值。本文综述了ZNF433的分子结构、生物学功能及其在前列腺癌和肾透明细胞癌中的作用机制,并探讨了其作为癌症生物标志物和治疗靶点的潜力。未来,进一步解析ZNF433的直接靶基因、上游调控机制及其与肿瘤微环境的相互作用,将有助于深入理解其在癌症中的功能,并为精准治疗提供新的策略。Krüppel-Associated Box Zinc Finger Proteins (KRAB-ZFPs) are the largest family of transcription factors in the human genome, extensively involved in gene expression regulation, development, and modulation of cellular signaling pathways. Zinc Finger Protein 433 (ZNF433) is a member of the KRAB-ZFPs family, but its molecular function and role in cancer have not been fully elucidated. In prostate cancer, ZNF433 overexpression promotes the formation of the β-catenin/TCF complex, activating the Wnt/β-catenin signaling pathway, which subsequently enhances cancer cell proliferation and migration, functioning as an oncogene. In contrast, in clear cell renal cell carcinoma, ZNF433 expression is downregulated, and its low expression is associated with higher tumor grade, advanced stage, and poorer prognosis. This downregulation may be linked to promoter hypermethylation, leading to transcriptional silencing, thereby influencing tumorigenesis and progression, functioning as a tumor suppressor. Moreover, abnormal expression of ZNF433 is closely correlated with clinical prognosis in cancer patients, suggesting its potential application in cancer diagnosis and therapy. This review summarizes the molecular structure, biological functions, and roles of ZNF433 in prostate cancer and ccRCC, while also exploring its potential as a biomarker and therapeutic target for cancer. In the future, further elucidation of ZNF433’s direct target genes, upstream regulatory mechanisms, and interactions with the tumor microenvironment will help deepen our understanding of its role in cancer and provide new strategies for precision therapy.
