Emerging evidence has suggested global histone H4 acetylation status plays an important role in neural plasticity. For instance, the imbalance of this epigenetic marker has been hypothesized as a key factor for the de...Emerging evidence has suggested global histone H4 acetylation status plays an important role in neural plasticity. For instance, the imbalance of this epigenetic marker has been hypothesized as a key factor for the development and progression of several neurological diseases. Likewise, astrocytic reactivity-a wellknown process that markedly influences the tissue remodeling after a central nervous system injury-is crucial for tissue remodeling after spinal cord injury（SCI）. However, the linkage between the above-mentioned mechanisms after SCI remains poorly understood. We sought to investigate the relation between both glial fibrillary acidic protein（GFAP） and S100 calcium-binding protein B（S100B）（astrocytic reactivity classical markers） and global histone H4 acetylation levels. Sixty-one male Wistar rats（aged ~3 months） were divided into the following groups： sham; 6 hours post-SCI; 24 hours post-SCI; 48 hours post-SCI; 72 hours post-SCI; and 7 days post-SCI. The results suggested that GFAP, but not S100B was associated with global histone H4 acetylation levels. Moreover, global histone H4 acetylation levels exhibited a complex pattern after SCI, encompassing at least three clearly defined phases（first phase： no changes in the 6, 24 and 48 hours post-SCI groups; second phase： increased levels in the 72 hours post-SCI group; and a third phase： return to levels similar to control in the 7 days post-SCI group）. Overall, these findings suggest global H4 acetylation levels exhibit distinct patterns of expression during the first week post-SCI, which may be associated with GFAP levels in the perilesional tissue. Current data encourage studies using H4 acetylation as a possible biomarker for tissue remodeling after spinal cord injury.展开更多
Eukaryotic chromatin consisting of nucleosomes connected by linker DNA is organized into higher order structures,which is facilitated by linker histone H1.Formation of chromatin compacts and protects the genome,but al...Eukaryotic chromatin consisting of nucleosomes connected by linker DNA is organized into higher order structures,which is facilitated by linker histone H1.Formation of chromatin compacts and protects the genome,but also hinders DNA transactions.Cells have evolved mechanisms to modify/remodel chromatin resulting in chromatin states suitable for genome functions.The high mobility group box(HMGB)proteins are non-histone chromatin architectural factors characterized by one or more HMGB motifs that bind DNA in a sequence nonspecific fashion.They play a major role in chromatin dynamics.The Saccharomyces cerevisiae(yeast hereafter)HMGB protein Hmo1 contains two HMGB motifs.However,unlike a canonical HMGB protein that has an acidic C-terminus,Hmo1 ends with a lysine rich,basic,C-terminus,resembling linker histone H1.Hmo1 exhibits characteristics of both HMGB proteins and linker histones in its multiple functions.For instance,Hmo1 promotes transcription by RNA polymerases I and II like canonical HMGB proteins but makes chromatin more compact/stable like linker histones.Recent studies have demonstrated that Hmo1 destabilizes/disrupts nucleosome similarly as other HMGB proteins in vitro and acts to maintain a common topological architecture of genes in yeast genome.This minireview reviews the functions of Hmo1 and the underlying mechanisms,highlighting recent discoveries.展开更多
Histone mimicry(HM)refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins.These motifs have the potential to interfere with host cell epigenome and counter...Histone mimicry(HM)refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins.These motifs have the potential to interfere with host cell epigenome and counteract antiviral response.Recent research shows that HM is critical for the pathogenesis and transmissibility of influenza virus and coronavirus.However,the distribution,characteristics,and functions of HM in eukaryotic viruses remain obscure.Herein,we developed a bioinformatic pipeline,Histone Motif Scan(HiScan),to identify HM motifs in viral proteins and predict their functions in silico.By analyzing 592,643 viral proteins using HiScan,we found that putative HM motifs were widely distributed in most viral proteins.Among animal viruses,the ratio of HM motifs between DNA viruses and RNA viruses was approximately 1.9:1,and viruses with smaller genomes had a higher density of HM motifs.Notably,coronaviruses exhibited an uneven distribution of HM motifs,with betacoronaviruses(including most human pathogenic coronaviruses)harboring more HM motifs than other coronaviruses,primarily in the NSP3,S,and N proteins.In summary,our virome-wide screening of HM motifs using HiScan revealed extensive but uneven distribution of HM motifs in most viral proteins,with a preference in DNA viruses.Viral HM may play an important role in modulating viral pathogenicity and virus-host interactions,making it an attractive area of research in virology and antiviral medication.展开更多
Histone deacetylases （HDACs） and histone acetyl transferases （HATs） are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained...Histone deacetylases （HDACs） and histone acetyl transferases （HATs） are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained in the N-terminal extensions of the core histones. Acetylation of histones affects gene expression through its influence on chromatin conformation. In addition, several non-histone proteins are regulated in their stability or biological function by the acetylation state of specific lysine residues. HDACs intervene in a multitude of biological processes and are part of a multiprotein family in which each member has its specialized functions. In addition, HDAC activity is tightly controlled through targeted recruitment, protein-protein interactions and post-translational modifications. Control of cell cycle progression, cell survival and differentiation are among the most important roles of these enzymes. Since these processes are affected by malignant transformation, HDAC inhibitors were developed as antineoplastic drugs and are showing encouraging efficacy in cancer patients.展开更多
Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused ...Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes,by interfering with the acetylation status of nuclear histone proteins,hence the name histone deacetylase inhibitors was coined.Yet,this view could not explain the high specificity for tumor cells and recent evidence now suggests that non-histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation,survival and cell death induction.展开更多
Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play ...Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.展开更多
Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain （PHD） finger protein 8 （PHF8） are associated with X-linked m...Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain （PHD） finger protein 8 （PHF8） are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without α-ketoglutarate （α-KG） at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di- and mono-methylated histone H3 lysine 9 （H3K9me2/1）, but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.展开更多
It is shown here that one can induce prematurely condensed chromosomes (PCCs) in G1-phase human (HeLa) and mouse (FT210) cells by treating them with the protein phosphatase inhibitor calyculin A. However, histone H1 i...It is shown here that one can induce prematurely condensed chromosomes (PCCs) in G1-phase human (HeLa) and mouse (FT210) cells by treating them with the protein phosphatase inhibitor calyculin A. However, histone H1 is not phosphorylated in these G1-PCCs. It has previously been proposed that histone H1 phosphorylation is responsible for mitotic chromosome condensation, but our results suggest that this is not the case. They indicate instead that phosphorylation of histone H1 is not required for chromosome condensation. It is known that the Cdk1 protein kinase, which triggers mitosis and also phosphorylates histone H1, cannot be activated in G1-phase because mitotic cyclins are not present. Since calyculin A induces PCCs in G1-phase in the absence of active Cdk1, our results suggest that inactivation of protein phosphatases may be just as important for the onset of chromosome condensation and other mitotic events as the activation of protein kinases.展开更多
组蛋白甲基化转移酶SET和MYND结构域蛋白3(SET and MYND domain-containing protein 3,SMYD3)是催化组蛋白和非组蛋白底物甲基化的酶,在许多生物学环境中发挥关键作用,如肌肉发育和部分癌症的进展。本综述对SMYD3进行相关的基本介绍,并...组蛋白甲基化转移酶SET和MYND结构域蛋白3(SET and MYND domain-containing protein 3,SMYD3)是催化组蛋白和非组蛋白底物甲基化的酶,在许多生物学环境中发挥关键作用,如肌肉发育和部分癌症的进展。本综述对SMYD3进行相关的基本介绍,并探讨SMYD3在肺癌中的研究,旨在为SMYD3在肺癌中的进一步研究提供依据。展开更多
基金supported by Brazilian funding agencies CNPq,CAPES and FAPERGS
文摘Emerging evidence has suggested global histone H4 acetylation status plays an important role in neural plasticity. For instance, the imbalance of this epigenetic marker has been hypothesized as a key factor for the development and progression of several neurological diseases. Likewise, astrocytic reactivity-a wellknown process that markedly influences the tissue remodeling after a central nervous system injury-is crucial for tissue remodeling after spinal cord injury（SCI）. However, the linkage between the above-mentioned mechanisms after SCI remains poorly understood. We sought to investigate the relation between both glial fibrillary acidic protein（GFAP） and S100 calcium-binding protein B（S100B）（astrocytic reactivity classical markers） and global histone H4 acetylation levels. Sixty-one male Wistar rats（aged ~3 months） were divided into the following groups： sham; 6 hours post-SCI; 24 hours post-SCI; 48 hours post-SCI; 72 hours post-SCI; and 7 days post-SCI. The results suggested that GFAP, but not S100B was associated with global histone H4 acetylation levels. Moreover, global histone H4 acetylation levels exhibited a complex pattern after SCI, encompassing at least three clearly defined phases（first phase： no changes in the 6, 24 and 48 hours post-SCI groups; second phase： increased levels in the 72 hours post-SCI group; and a third phase： return to levels similar to control in the 7 days post-SCI group）. Overall, these findings suggest global H4 acetylation levels exhibit distinct patterns of expression during the first week post-SCI, which may be associated with GFAP levels in the perilesional tissue. Current data encourage studies using H4 acetylation as a possible biomarker for tissue remodeling after spinal cord injury.
文摘Eukaryotic chromatin consisting of nucleosomes connected by linker DNA is organized into higher order structures,which is facilitated by linker histone H1.Formation of chromatin compacts and protects the genome,but also hinders DNA transactions.Cells have evolved mechanisms to modify/remodel chromatin resulting in chromatin states suitable for genome functions.The high mobility group box(HMGB)proteins are non-histone chromatin architectural factors characterized by one or more HMGB motifs that bind DNA in a sequence nonspecific fashion.They play a major role in chromatin dynamics.The Saccharomyces cerevisiae(yeast hereafter)HMGB protein Hmo1 contains two HMGB motifs.However,unlike a canonical HMGB protein that has an acidic C-terminus,Hmo1 ends with a lysine rich,basic,C-terminus,resembling linker histone H1.Hmo1 exhibits characteristics of both HMGB proteins and linker histones in its multiple functions.For instance,Hmo1 promotes transcription by RNA polymerases I and II like canonical HMGB proteins but makes chromatin more compact/stable like linker histones.Recent studies have demonstrated that Hmo1 destabilizes/disrupts nucleosome similarly as other HMGB proteins in vitro and acts to maintain a common topological architecture of genes in yeast genome.This minireview reviews the functions of Hmo1 and the underlying mechanisms,highlighting recent discoveries.
基金funded by the National Natural Science Foundation of China(No.U2002218,32270170 and 81902070)the Fund of Hunan University(521119400156)the Science and Technology Innovation Program of Hunan Province(2024RC1028).
文摘Histone mimicry(HM)refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins.These motifs have the potential to interfere with host cell epigenome and counteract antiviral response.Recent research shows that HM is critical for the pathogenesis and transmissibility of influenza virus and coronavirus.However,the distribution,characteristics,and functions of HM in eukaryotic viruses remain obscure.Herein,we developed a bioinformatic pipeline,Histone Motif Scan(HiScan),to identify HM motifs in viral proteins and predict their functions in silico.By analyzing 592,643 viral proteins using HiScan,we found that putative HM motifs were widely distributed in most viral proteins.Among animal viruses,the ratio of HM motifs between DNA viruses and RNA viruses was approximately 1.9:1,and viruses with smaller genomes had a higher density of HM motifs.Notably,coronaviruses exhibited an uneven distribution of HM motifs,with betacoronaviruses(including most human pathogenic coronaviruses)harboring more HM motifs than other coronaviruses,primarily in the NSP3,S,and N proteins.In summary,our virome-wide screening of HM motifs using HiScan revealed extensive but uneven distribution of HM motifs in most viral proteins,with a preference in DNA viruses.Viral HM may play an important role in modulating viral pathogenicity and virus-host interactions,making it an attractive area of research in virology and antiviral medication.
文摘Histone deacetylases （HDACs） and histone acetyl transferases （HATs） are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained in the N-terminal extensions of the core histones. Acetylation of histones affects gene expression through its influence on chromatin conformation. In addition, several non-histone proteins are regulated in their stability or biological function by the acetylation state of specific lysine residues. HDACs intervene in a multitude of biological processes and are part of a multiprotein family in which each member has its specialized functions. In addition, HDAC activity is tightly controlled through targeted recruitment, protein-protein interactions and post-translational modifications. Control of cell cycle progression, cell survival and differentiation are among the most important roles of these enzymes. Since these processes are affected by malignant transformation, HDAC inhibitors were developed as antineoplastic drugs and are showing encouraging efficacy in cancer patients.
基金Supported by Supported by a Research Grant of the University Medical Center Giessen and Marburg
文摘Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes,by interfering with the acetylation status of nuclear histone proteins,hence the name histone deacetylase inhibitors was coined.Yet,this view could not explain the high specificity for tumor cells and recent evidence now suggests that non-histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation,survival and cell death induction.
文摘Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.
基金Supplementary information is linked to the online version of the paper on the Cell Research website.Acknowledgments We thank Dr Dawei Li （China Agricultural University） for generously providing us with the experimental conditions during the early stages of this project. We thank Dr Ruiming Xu （Institute of Biophysics, Chinese Academy of Sciences） for critical reading of this manuscript and advice. We thank Dr Pinchao Mei （Chinese Academy of Medical Sciences and Peking Union Medical College）, Xinqi Liu （Nankai University） and Jiemin Wong （East China Normal University） for discussions and advice. The synchrotronradiation experiments were performed at Shanghai Synchrotron Radiation Facility （SSRF） and NE3A in the Photon Factory. Z.C. is supported by the National Basic Research Program of China （973 Program, 2009CB825501）, the National Natural Science Foundation of China （30870494 and 90919043）, the New Century Excellent Talents in University （NCET-07-0808） and the Innovative Project of SKLAB. S. H. is supported by the National Key Laboratory Special Fund 2060204. Z. D. is supported by the National Natural Science Foundation of China （J0730639）.
文摘Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain （PHD） finger protein 8 （PHF8） are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without α-ketoglutarate （α-KG） at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di- and mono-methylated histone H3 lysine 9 （H3K9me2/1）, but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.
文摘It is shown here that one can induce prematurely condensed chromosomes (PCCs) in G1-phase human (HeLa) and mouse (FT210) cells by treating them with the protein phosphatase inhibitor calyculin A. However, histone H1 is not phosphorylated in these G1-PCCs. It has previously been proposed that histone H1 phosphorylation is responsible for mitotic chromosome condensation, but our results suggest that this is not the case. They indicate instead that phosphorylation of histone H1 is not required for chromosome condensation. It is known that the Cdk1 protein kinase, which triggers mitosis and also phosphorylates histone H1, cannot be activated in G1-phase because mitotic cyclins are not present. Since calyculin A induces PCCs in G1-phase in the absence of active Cdk1, our results suggest that inactivation of protein phosphatases may be just as important for the onset of chromosome condensation and other mitotic events as the activation of protein kinases.
文摘目的分析血清微小核糖核酸(micro RNA,miR)-139-5p,组蛋白去乙酰化酶4(histone deacetylase 4,HDAC4)和胶质纤维酸性蛋白(glialfibrillary acidic protein,GFAP)与新生儿缺氧缺血性脑病(hypoxic-ischemic encephalopathy,HIE)脑损伤严重程度的关系。方法选取2017年1月~2022年3月广元市中心医院分娩的HIE新生儿72例为研究对象(研究组);同期健康的足月新生儿75例为对照组。实时荧光定量PCR检测血清中miR-139-5p,HDAC4表达水平。酶联免疫吸附法(ELISA)检测血清GFAP水平。Logistic回归分析影响HIE患儿重度脑损伤发生的因素。结果与对照组相比,研究组血清GFAP(1.30±0.37ng/L vs 0.50±0.15ng/L),HDAC4相对表达水平(2.05±0.39 vs 1.02±0.21)升高,miR-139-5p相对表达水平(0.63±0.14 vs 1.01±0.22)和NBNA评分(33.20±1.43分vs 39.85±2.23分)降低,差异具有统计学意义(t=17.304,20.046,12.436,21.424,均P<0.05);与轻中度组相比,重度组血清GFAP(1.61±0.47ng/L vs 1.16±0.33ng/L),HDAC4(2.43±0.37 vs 1.87±0.40)相对表达水平升高,miR-139-5p相对表达水平(0.38±0.10 vs 0.74±0.16)和NBNA评分(30.52±1.54分vs 34.46±1.38分)降低,差异具有统计学意义(t=4.690,5.669,9.900,10.884,均P<0.05)。Logistic回归分析显示,miR-139-5p低表达,HDAC4高表达,低NBNA评分,低出生后1 min内Apgar评分是影响HIE患儿重度脑损伤发生的危险因素(Waldχ^(2)=5.772~6.969,OR=1.519~1.709,均P<0.05)。Pearson分析显示,血清miR-139-5p表达水平与GFAP,HDAC4呈负相关(r=-0.416,-0.579,均P<0.05),血清HDAC4表达水平与GFAP呈正相关(r=0.437,P<0.05)。Spearman分析显示,血清mi R-139-5p表达水平与NBNA评分、出生后1 min内Apgar评分、出生后5 min内Apgar评分呈正相关(r=0.398,0.367,0.348,均P<0.05);血清HDAC4表达水平与NBNA评分、出生后1 min内Apgar评分、出生后5 min内Apgar评分呈负相关(r=-0.364,-0.345,-0.332,均P<0.05)。结论HIE患儿血清中miR-139-5p表达降低,HDAC4表达升高,mi R-139-5p,HDAC4与HIE患儿脑损伤严重程度有关。
文摘组蛋白甲基化转移酶SET和MYND结构域蛋白3(SET and MYND domain-containing protein 3,SMYD3)是催化组蛋白和非组蛋白底物甲基化的酶,在许多生物学环境中发挥关键作用,如肌肉发育和部分癌症的进展。本综述对SMYD3进行相关的基本介绍,并探讨SMYD3在肺癌中的研究,旨在为SMYD3在肺癌中的进一步研究提供依据。
