目的探讨ASF1B基因在肾透明细胞癌患者中的表达水平及对临床预后的意义。方法通过在肿瘤基因图谱(the cancer genome atlas,TCGA)及UCSC Xena数据库下载并分析肾透明细胞癌基因表达数据共607例,其中正常肾组织及癌旁组织数据72例,肾透...目的探讨ASF1B基因在肾透明细胞癌患者中的表达水平及对临床预后的意义。方法通过在肿瘤基因图谱(the cancer genome atlas,TCGA)及UCSC Xena数据库下载并分析肾透明细胞癌基因表达数据共607例,其中正常肾组织及癌旁组织数据72例,肾透明细胞癌数据535例。明确ASF1B基因在肾透明细胞癌组织与正常组织间的表达差异,分析ASF1B表达与患者生存时间的相关性。使用生信线上工具(GEPIA、cBioPortal、STRING以及TIMER)探究肾透明细胞癌患者ASF1B表达与基因突变及甲基化水平相关性,研讨其与肿瘤免疫微环境的相互作用,探讨ASF1B对肾透明细胞癌的预测能力。结果ASF1B基因在肾透明细胞癌细胞中表达水平明显高于正常肾组织中的表达水平(P=2.22e^(-16));ASF1B基因高表达组的患者生存周期明显低于ASF1B基因低表达组(P=0.024)。ASF1B基因在经过多因素回归分析(P<0.001)后可确定为肾透明细胞癌的高风险独立预后因子。ASF1B基因突变水平无法作为患者预后的诊断指标;cg06969527甲基化位点的甲基化程度与基因表达呈负相关(P=0.0048,HR=-0.16)。ASF1B基因表达水平与CD4^(+)T细胞表达水平呈负相关(P=5.89e^(-1),Rho=-0.025),与CD8^(+)T细胞表达水平呈正相关(P=2.04e^(-10),Rho=0.29),与CD2基因表达水平呈正相关(P=2.47e^(-21),Rho=0.395),与CD3D基因表达水平呈正相关(P=9.54e^(-22),Rho=0.399),与CD3E基因表达水平呈正相关(P=1.58e^(-20),Rho=0.387)。结论ASF1B基因与肾透明细胞癌患者的不良预后有关,可以作为肾透明细胞癌的独立危险因素。展开更多
目的:应用生物信息学技术分析组蛋白伴侣抗沉默功能蛋白1B(anti-silencing function 1B,ASF1B)在胶质母细胞瘤中的表达水平以及与患者预后的相关性。方法:通过下载TCGA数据和GEPIA数据库分析了ASF1B在胶质母细胞瘤以及低级别胶质瘤中的...目的:应用生物信息学技术分析组蛋白伴侣抗沉默功能蛋白1B(anti-silencing function 1B,ASF1B)在胶质母细胞瘤中的表达水平以及与患者预后的相关性。方法:通过下载TCGA数据和GEPIA数据库分析了ASF1B在胶质母细胞瘤以及低级别胶质瘤中的表达水平,通过CCLE数据库和HPA数据库在线分析了ASF1B在胶质瘤细胞株以及组织中的表达状态,通过PrognoScan数据库分析了ASF1B与胶质瘤患者预后的相关性。结果显示:ASF1B在胶质瘤中表达上调,并且与低级别胶质瘤相比,ASF1B在胶质母细胞瘤中具有更高的表达水平。ASF1B在胶质瘤中的表达高于多数肿瘤,并且ASF1B在高级别胶质瘤组织中蛋白表达增强。PrognoScan数据表明ASF1B与胶质瘤患者不良预后相关。展开更多
Endothelial-to-mesenchymal transition(EndMT)is a key driver of atherosclerosis.Aerobic glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate levels.Histone lactylation,mediate...Endothelial-to-mesenchymal transition(EndMT)is a key driver of atherosclerosis.Aerobic glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate levels.Histone lactylation,mediated by lactate,can regulate gene expression and participate in disease regulation.However,whether histone lactylation is involved in atherosclerosis remains unknown.Here,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’arteries.Mechanistically,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting EndMT.We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction.Functional analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development.Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced atherosclerosis.This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.展开更多
Most fungi display a mixed mating system with both asexual and sexual reproduction.The timing of the two modes of reproduction must be carefully coordinated through signal perception and coordination in the cell along...Most fungi display a mixed mating system with both asexual and sexual reproduction.The timing of the two modes of reproduction must be carefully coordinated through signal perception and coordination in the cell along with chromatin modification.Here,we investigated coordination of reproductive output by investigating the function of the histone chaper-one anti-silencing factor 1(ASF1)in a fungal species amenable to characterization of both asexual and sexual reproduction.We used knockout approach to show that SeASF1 influenced asexual and sexual reproduction in Stemphylium eturmiunum.SeASF1-deleted strains failed to produce pseudothecia,but produce abnormal conidia and showed an irregular distribution of nuclei in mycelium.Transcriptome sequencing was then used to identify genes with altered expression in the SeASF1-deleted strains.The transcriptional expression of the identified SeDJ-1 was strongly regulated by SeASF1.The interaction of SeDJ-1 and SeASF1 was confirmed using Y2H,Co-IP,and pull-down.Due to some components of phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)signaling pathway were known to interact with DJ-1 in mammals,we verified SePI3K,an element of PI3K/AKT signaling pathway in S.eturmiunum,was directly linked to SeDJ-1 and then these two proteins were defined as a coordinator of reproduction.However,knockout of SeDJ-1 or SePI3K altered the asexual and sexual repro-duction,but SePI3K recovered the asexual and sexual development of∆Sedj-1.The SeDJ-1-M6 segment of SeDJ-1 was essential for its interaction with SePI3K and played a critical role in restoring sexual reproduction in the∆Sepi3k,providing a deep understanding of the regulatory mechanism of SeDJ-1 in S.eturmiunum development.Summarily,SeASF1 is able to trigger SeDJ-1 and SeDJ-1can also activate SePI3K,which is orchestrally involved in asexual and sexual reproduction in S.eturmiunum.All these results reveal that SeASF1 manipulates asexual and sexual reproduction in S.eturmiunum by SeDJ-1 perception of PI3K/AKT signaling pathway.These data highlight the deep similarities in coordinating asexual and sexual processes in both fungi and eukaryotes in general.展开更多
Epigenetic information carried by histone modifications not only reflects the state of gene expression,but also participates in the maintenance of chromatin states and the regulation of gene expression.Recycling of pa...Epigenetic information carried by histone modifications not only reflects the state of gene expression,but also participates in the maintenance of chromatin states and the regulation of gene expression.Recycling of parental histones to daughter chromatin after DNA replication is vital to mitotic inheritance of epigenetic information and the maintenance of cell identity,because the locus-specific modifications of the parental histones need to be maintained.To assess the precision of parental histone recycling,we developed a synthetic local label-chasing system in budding yeast Saccharomyces cerevisiae.Using this system,we observed that parental histone H3 can be recycled to their original position,thereby recovering their position information after DNA replication at all tested loci,including heterochromatin boundary,non-transcribed region,and actively transcribed regions.Moreover,the recycling rate appears to be affected by local chromatin environment.We surveyed a number of potential regulatory factors and observed that histone H3-H4 chaperon Asf1 contributed to parental histone recycling,while the eukaryotic replisome-associated components Mcm2 and Dpb3 displayed compounding effects in this process.In addition,the FACT complex also plays a role in the recycling of parental histones and helps to stabilize the nucleosomes.展开更多
The structural basis for histone recognition by the histone chaperone nuclear autoantigenic sperm protein(NASP)remains largely unclear.Here,we showed that Arabidopsis thaliana AtNASP is a monomer and displays robust n...The structural basis for histone recognition by the histone chaperone nuclear autoantigenic sperm protein(NASP)remains largely unclear.Here,we showed that Arabidopsis thaliana AtNASP is a monomer and displays robust nucleosome assembly activity in vitro.Examining the structure of AtNASP complexed with a histone H3α3 peptide revealed a binding mode that is conserved in human NASP.AtNASP recognizes the H3 N-terminal region distinct from human NASP.Moreover,AtNASP forms a co-chaperone complex with ANTI-SILENCING FUNCTION 1 ASF1 by binding to the H3 Nterminal region.Therefore,we deciphered the structure of AtNASP and the basis of the AtNASP-H3 interaction.展开更多
文摘目的探讨ASF1B基因在肾透明细胞癌患者中的表达水平及对临床预后的意义。方法通过在肿瘤基因图谱(the cancer genome atlas,TCGA)及UCSC Xena数据库下载并分析肾透明细胞癌基因表达数据共607例,其中正常肾组织及癌旁组织数据72例,肾透明细胞癌数据535例。明确ASF1B基因在肾透明细胞癌组织与正常组织间的表达差异,分析ASF1B表达与患者生存时间的相关性。使用生信线上工具(GEPIA、cBioPortal、STRING以及TIMER)探究肾透明细胞癌患者ASF1B表达与基因突变及甲基化水平相关性,研讨其与肿瘤免疫微环境的相互作用,探讨ASF1B对肾透明细胞癌的预测能力。结果ASF1B基因在肾透明细胞癌细胞中表达水平明显高于正常肾组织中的表达水平(P=2.22e^(-16));ASF1B基因高表达组的患者生存周期明显低于ASF1B基因低表达组(P=0.024)。ASF1B基因在经过多因素回归分析(P<0.001)后可确定为肾透明细胞癌的高风险独立预后因子。ASF1B基因突变水平无法作为患者预后的诊断指标;cg06969527甲基化位点的甲基化程度与基因表达呈负相关(P=0.0048,HR=-0.16)。ASF1B基因表达水平与CD4^(+)T细胞表达水平呈负相关(P=5.89e^(-1),Rho=-0.025),与CD8^(+)T细胞表达水平呈正相关(P=2.04e^(-10),Rho=0.29),与CD2基因表达水平呈正相关(P=2.47e^(-21),Rho=0.395),与CD3D基因表达水平呈正相关(P=9.54e^(-22),Rho=0.399),与CD3E基因表达水平呈正相关(P=1.58e^(-20),Rho=0.387)。结论ASF1B基因与肾透明细胞癌患者的不良预后有关,可以作为肾透明细胞癌的独立危险因素。
文摘目的:应用生物信息学技术分析组蛋白伴侣抗沉默功能蛋白1B(anti-silencing function 1B,ASF1B)在胶质母细胞瘤中的表达水平以及与患者预后的相关性。方法:通过下载TCGA数据和GEPIA数据库分析了ASF1B在胶质母细胞瘤以及低级别胶质瘤中的表达水平,通过CCLE数据库和HPA数据库在线分析了ASF1B在胶质瘤细胞株以及组织中的表达状态,通过PrognoScan数据库分析了ASF1B与胶质瘤患者预后的相关性。结果显示:ASF1B在胶质瘤中表达上调,并且与低级别胶质瘤相比,ASF1B在胶质母细胞瘤中具有更高的表达水平。ASF1B在胶质瘤中的表达高于多数肿瘤,并且ASF1B在高级别胶质瘤组织中蛋白表达增强。PrognoScan数据表明ASF1B与胶质瘤患者不良预后相关。
基金supported by the National Natural Science Foundation of China(82270421,81970428,31771334,81800385,82270484,82370376,82121001,82030013,and 82241211)Major Research Plan of the National Natural Science Foundation of China(91649125)+3 种基金the National Key R&D Program of China(2019YFA0802704)The major project of Natural Science Foundation of the Jiangsu Higher Education Institution of China(21KJA310006)Jiangsu Provincial Social Development Project(BE2021749,China)Special Program for Top Innovative Talents(NJMUTY20230082,China).
文摘Endothelial-to-mesenchymal transition(EndMT)is a key driver of atherosclerosis.Aerobic glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate levels.Histone lactylation,mediated by lactate,can regulate gene expression and participate in disease regulation.However,whether histone lactylation is involved in atherosclerosis remains unknown.Here,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’arteries.Mechanistically,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting EndMT.We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction.Functional analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development.Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced atherosclerosis.This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.
基金Funding was provided by National Natural Science Foundation of China(Grant nos.31230001,U200220015).
文摘Most fungi display a mixed mating system with both asexual and sexual reproduction.The timing of the two modes of reproduction must be carefully coordinated through signal perception and coordination in the cell along with chromatin modification.Here,we investigated coordination of reproductive output by investigating the function of the histone chaper-one anti-silencing factor 1(ASF1)in a fungal species amenable to characterization of both asexual and sexual reproduction.We used knockout approach to show that SeASF1 influenced asexual and sexual reproduction in Stemphylium eturmiunum.SeASF1-deleted strains failed to produce pseudothecia,but produce abnormal conidia and showed an irregular distribution of nuclei in mycelium.Transcriptome sequencing was then used to identify genes with altered expression in the SeASF1-deleted strains.The transcriptional expression of the identified SeDJ-1 was strongly regulated by SeASF1.The interaction of SeDJ-1 and SeASF1 was confirmed using Y2H,Co-IP,and pull-down.Due to some components of phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)signaling pathway were known to interact with DJ-1 in mammals,we verified SePI3K,an element of PI3K/AKT signaling pathway in S.eturmiunum,was directly linked to SeDJ-1 and then these two proteins were defined as a coordinator of reproduction.However,knockout of SeDJ-1 or SePI3K altered the asexual and sexual repro-duction,but SePI3K recovered the asexual and sexual development of∆Sedj-1.The SeDJ-1-M6 segment of SeDJ-1 was essential for its interaction with SePI3K and played a critical role in restoring sexual reproduction in the∆Sepi3k,providing a deep understanding of the regulatory mechanism of SeDJ-1 in S.eturmiunum development.Summarily,SeASF1 is able to trigger SeDJ-1 and SeDJ-1can also activate SePI3K,which is orchestrally involved in asexual and sexual reproduction in S.eturmiunum.All these results reveal that SeASF1 manipulates asexual and sexual reproduction in S.eturmiunum by SeDJ-1 perception of PI3K/AKT signaling pathway.These data highlight the deep similarities in coordinating asexual and sexual processes in both fungi and eukaryotes in general.
基金supported by the National Key Research and Development Program of China(2019YFA0508900)the National Natural Science Foundation of China(32170608,32288102)+1 种基金the K.C.Wong Educational Foundation(GJTD-2020-06)supported by the Youth Innovation Promotion Association(2017133,2020097)of the Chinese Academy of Sciences。
文摘Epigenetic information carried by histone modifications not only reflects the state of gene expression,but also participates in the maintenance of chromatin states and the regulation of gene expression.Recycling of parental histones to daughter chromatin after DNA replication is vital to mitotic inheritance of epigenetic information and the maintenance of cell identity,because the locus-specific modifications of the parental histones need to be maintained.To assess the precision of parental histone recycling,we developed a synthetic local label-chasing system in budding yeast Saccharomyces cerevisiae.Using this system,we observed that parental histone H3 can be recycled to their original position,thereby recovering their position information after DNA replication at all tested loci,including heterochromatin boundary,non-transcribed region,and actively transcribed regions.Moreover,the recycling rate appears to be affected by local chromatin environment.We surveyed a number of potential regulatory factors and observed that histone H3-H4 chaperon Asf1 contributed to parental histone recycling,while the eukaryotic replisome-associated components Mcm2 and Dpb3 displayed compounding effects in this process.In addition,the FACT complex also plays a role in the recycling of parental histones and helps to stabilize the nucleosomes.
基金the National Key R&D Program of China(2018YFC1004500)the Natural Science Foundation of Guangdong Province(2022A1515010501)+4 种基金the Chinese National Natural Science Foundation(32171206 and 31800619)the Shenzhen Science and Technology Program(KQTD20190929173906742)Key Laboratory of Molecular Design for Plant Cel Factory of Guangdong Higher Education Institutes(2019KSYS006)the Shenzhen Government‘Peacock Plan’(Y01226136)the Thousand Young Talents Program。
文摘The structural basis for histone recognition by the histone chaperone nuclear autoantigenic sperm protein(NASP)remains largely unclear.Here,we showed that Arabidopsis thaliana AtNASP is a monomer and displays robust nucleosome assembly activity in vitro.Examining the structure of AtNASP complexed with a histone H3α3 peptide revealed a binding mode that is conserved in human NASP.AtNASP recognizes the H3 N-terminal region distinct from human NASP.Moreover,AtNASP forms a co-chaperone complex with ANTI-SILENCING FUNCTION 1 ASF1 by binding to the H3 Nterminal region.Therefore,we deciphered the structure of AtNASP and the basis of the AtNASP-H3 interaction.
