Wnt and its crosstalk signaling pathways are involved in the modulating ischemia‒reperfusion(I/R)injury.However,whether Wnt2 is a novel therapeutic agent for I/R injury is largely unknown.Here,we show that the downreg...Wnt and its crosstalk signaling pathways are involved in the modulating ischemia‒reperfusion(I/R)injury.However,whether Wnt2 is a novel therapeutic agent for I/R injury is largely unknown.Here,we show that the downregulation of serum Wnt2 levels in acute myocardial infarction(AMI)patients following reperfusion therapy,and Wnt2 levels are inversely correlated with the levels of myocardial injury markers(cTnT and CK-MB).Therapeutic administration of recombinant Wnt2 protein(rbWnt2)alleviates cardiac I/R injury and improves cardiac function by suppressing ROS levels and cardiomyocyte death in mice.Further analysis revealed that rbWnt2 downregulated Nap1L1 to reactivate the transcription of antioxidant genes(SOD,GPX,and UCP3)to reduce ROS levels and subsequently inhibit cardiomyocyte apoptosis and ferroptosis during the I/R process.Cardiac-specific Nap1L1 knockdown attenuated I/R injury,whereas overexpression of Nap1L1 partly abolished the cardiac protection mediated by rbWnt2 administration in the I/R model.Mechanistically,Wnt2 promoted Nap1L1 ubiquitination and degradation to restore ROS scavenging systems via Lrp6-mediated recruitment of the E3 ligase Trim11 in I/R hearts.Nap1L1 suppression plays a critical role in mediating the cardioprotective effects of rbWnt2.These findings establish Wnt2 as a therapeutic agent that targets compartmentalized oxidative damage,suggesting a novel strategy to mitigate I/R injury through the Lrp6/Trim11/Nap1L1 axis.展开更多
In eukaryotic cells,histones are packaged into octameric core particles with DNA wrapping around to form nucleosomes,which are the basic units of chromatin(Kornberg and Thomas,1974).Multicellular organisms utilise chr...In eukaryotic cells,histones are packaged into octameric core particles with DNA wrapping around to form nucleosomes,which are the basic units of chromatin(Kornberg and Thomas,1974).Multicellular organisms utilise chromatin marks to translate one single genome into hundreds of epigenomes for their corresponding cell types.Inheritance of epigenetic status is critical for the maintenance of gene expression profile during mitotic cell divisions(Allis et al.,2006).During S phase,canonical histones are deposited onto DNA in a replication-coupled manner(Allis et al.,2006).To understand how dividing cells overcome the dilution of epigenetic marks after chromatin duplication,DNA replication coupled(RC)nucleosome assembly has been of great interest.In this review,we focus on the potential influence of RC nucleosome assembly processes on the maintenance of epigenetic status.展开更多
In eukaryotic cells,the smallest subunit of chromatin is the nucleosome,which consists of a segment of DNA wound on histone protein cores. Despite many years of effort,the process of nucleosome assembly and disassembl...In eukaryotic cells,the smallest subunit of chromatin is the nucleosome,which consists of a segment of DNA wound on histone protein cores. Despite many years of effort,the process of nucleosome assembly and disassembly is still not very clear. Here,we present a convenient method to investigate the process of nucleosome assembly at the single molecule level. We invented a novel system derived from the yeast nucleoplasmic extracts(YNPE),and demonstrated that the YNPE supports the nucleosome assembly under physiological condition. By combining the total internal reflection fluorescence microscopy with microfluidic flow-cell technique,the dynamic process of nucleosome assembly in YNPE was visualized at single-molecule level. Our system provides a novel in vitro single-molecule tool to investigate the dynamics of nucleosome assembly under physiological conditions.展开更多
Subject Code:C05 With the support by the National Natural Science Foundation of China,the research team led by Dr.Li Qing(李晴)at the State Key Laboratory of Protein and Plant Gene Research,School of Life Sciences and...Subject Code:C05 With the support by the National Natural Science Foundation of China,the research team led by Dr.Li Qing(李晴)at the State Key Laboratory of Protein and Plant Gene Research,School of Life Sciences and Peking-Tsinghua Center for Life Sciences,Peking University,Beijing,recently reported that展开更多
Minichromosome Maintenance protein 10(MCM10)is essential for DNA replication initiation and DNA elongation in yeasts and animals.Although the functions of MCM10 in DNA replication and repair have been well documented,...Minichromosome Maintenance protein 10(MCM10)is essential for DNA replication initiation and DNA elongation in yeasts and animals.Although the functions of MCM10 in DNA replication and repair have been well documented,the detailed mechanisms for MCM10 in these processes are not well known.Here,we identified AtMCM10 gene through a forward genetic screening for releasing a silenced marker gene.Although plant MCM10 possesses a similar crystal structure as animal MCM10,AtMCM10 is not essential for plant growth or development in Arabidopsis.AtMCM10 can directly bind to histone H3-H4 and promotes nucleosome assembly in vitro.The nucleosome density is decreased in Atmcm10,and most of the nucleosome density decreased regions in Atmcm10 are also regulated by newly synthesized histone chaperone Chromatin Assembly Factor-1(CAF-1).Loss of both AtMCM10 and CAF-1 is embryo lethal,indicating that AtM CM10 and CAF-1 are indispensable for replication-coupled nucleosome assembly.AtMCM10 interacts with both new and parental histones.Atmcm10 mutants have lower H3.1abundance and reduced H3K27me1/3 levels with releasing some silenced transposons.We propose that AtM CM10 deposits new and parental histones during nucleosome assembly,maintaining proper epigenetic modifications and genome stability during DNA replication.展开更多
Chromatin structure is important for controlling gene expression, but mechanisms underlying chromatin remodel- ing are not fully understood. Here we report that an FKBP （FK506 binding protein） type immunophilin, AtF...Chromatin structure is important for controlling gene expression, but mechanisms underlying chromatin remodel- ing are not fully understood. Here we report that an FKBP （FK506 binding protein） type immunophilin, AtFKBP53, possesses histone chaperone activity and is required for repressing ribosomal gene expression in Arabidopsis. The At- FKBP53 protein is a multidomain FKBP with a typical peptidylprolyl isomerase （PPIase） domain and several highly charged domains. Using nucleosome assembly assays, we showed that AtFKBP53 has histone chaperone activity and the charged acidic domains are sufficient for the activity. We show that AtFKBP53 interacts with histone H3 through the acidic domains, whereas the PPIase domain is dispensable for histone chaperone activity or histone binding. Ri- bosomal RNA gene （18S rDNA） is overexpressed when AtFKBP53 activity is reduced or eliminated in Arabidopsis plants. Chromatin immunoprecipitation assay showed that AtFKBP53 is associated with the 18S rDNA gene chro- matin, implicating that AtFKBP53 represses rRNA genes at the chromatin level. This study identifies a new histone chaperone in plants that functions in chromatin remodeling and regulation of transcription.展开更多
The long-term effectiveness of targeted cancer therapies is limited by the development of resistance.Although epigenetic reprogramming has been implicated in resistance,the mechanisms remain elusive.Herein,we demonstr...The long-term effectiveness of targeted cancer therapies is limited by the development of resistance.Although epigenetic reprogramming has been implicated in resistance,the mechanisms remain elusive.Herein,we demonstrate that increased chromatin accessibility is involved in adaptive BRAF inhibitor(BRAFi)-resistance in melanoma cells.We observed loss of chromatin assembly factor 1(CAF-1)and its related histone H3 lysine 9 trimethylation(H3K9me3)with adaptive BRAFi resistance.We further showed that depletion of CAF-1 provides chromatin plasticity for effective reprogramming by AP1 components to promote BRAFi resistance.Our data sug-gest that therapeutic approaches to restore H3K9me3 levels may compensate for the loss of CAF-1 and,in turn,suppress resistance to BRAF inhibitors.展开更多
基金supported by the National Natural Science Foundation of China(Grants 82230009 and 82430016 to Z.Y.,82370255,U24A20646,and 81770239 to G.H.,82400310 to W.Y.)the National Key R&D Program of China(Grant 2023YFA1800601 to Z.Y.)+1 种基金the Noncommunicable Chronic Diseases-National Science and Technology Major Project(Grant 2023ZD0503203 to Z.Y.)the Shanghai Science and Technology Commission Project(Grant 23410761200 to G.H.).
文摘Wnt and its crosstalk signaling pathways are involved in the modulating ischemia‒reperfusion(I/R)injury.However,whether Wnt2 is a novel therapeutic agent for I/R injury is largely unknown.Here,we show that the downregulation of serum Wnt2 levels in acute myocardial infarction(AMI)patients following reperfusion therapy,and Wnt2 levels are inversely correlated with the levels of myocardial injury markers(cTnT and CK-MB).Therapeutic administration of recombinant Wnt2 protein(rbWnt2)alleviates cardiac I/R injury and improves cardiac function by suppressing ROS levels and cardiomyocyte death in mice.Further analysis revealed that rbWnt2 downregulated Nap1L1 to reactivate the transcription of antioxidant genes(SOD,GPX,and UCP3)to reduce ROS levels and subsequently inhibit cardiomyocyte apoptosis and ferroptosis during the I/R process.Cardiac-specific Nap1L1 knockdown attenuated I/R injury,whereas overexpression of Nap1L1 partly abolished the cardiac protection mediated by rbWnt2 administration in the I/R model.Mechanistically,Wnt2 promoted Nap1L1 ubiquitination and degradation to restore ROS scavenging systems via Lrp6-mediated recruitment of the E3 ligase Trim11 in I/R hearts.Nap1L1 suppression plays a critical role in mediating the cardioprotective effects of rbWnt2.These findings establish Wnt2 as a therapeutic agent that targets compartmentalized oxidative damage,suggesting a novel strategy to mitigate I/R injury through the Lrp6/Trim11/Nap1L1 axis.
基金supported by the National Programs for High Technology Research and Development Program(863 Program)(Grant No.2007AA02Z1A6,to B.Z.).
文摘In eukaryotic cells,histones are packaged into octameric core particles with DNA wrapping around to form nucleosomes,which are the basic units of chromatin(Kornberg and Thomas,1974).Multicellular organisms utilise chromatin marks to translate one single genome into hundreds of epigenomes for their corresponding cell types.Inheritance of epigenetic status is critical for the maintenance of gene expression profile during mitotic cell divisions(Allis et al.,2006).During S phase,canonical histones are deposited onto DNA in a replication-coupled manner(Allis et al.,2006).To understand how dividing cells overcome the dilution of epigenetic marks after chromatin duplication,DNA replication coupled(RC)nucleosome assembly has been of great interest.In this review,we focus on the potential influence of RC nucleosome assembly processes on the maintenance of epigenetic status.
基金supported by the National Natural Science Foundation of China (31371264)CAS Interdisciplinary Innovation Team and the Newton Advanced Fellowship (NA140085) from the Royal Society
文摘In eukaryotic cells,the smallest subunit of chromatin is the nucleosome,which consists of a segment of DNA wound on histone protein cores. Despite many years of effort,the process of nucleosome assembly and disassembly is still not very clear. Here,we present a convenient method to investigate the process of nucleosome assembly at the single molecule level. We invented a novel system derived from the yeast nucleoplasmic extracts(YNPE),and demonstrated that the YNPE supports the nucleosome assembly under physiological condition. By combining the total internal reflection fluorescence microscopy with microfluidic flow-cell technique,the dynamic process of nucleosome assembly in YNPE was visualized at single-molecule level. Our system provides a novel in vitro single-molecule tool to investigate the dynamics of nucleosome assembly under physiological conditions.
文摘Subject Code:C05 With the support by the National Natural Science Foundation of China,the research team led by Dr.Li Qing(李晴)at the State Key Laboratory of Protein and Plant Gene Research,School of Life Sciences and Peking-Tsinghua Center for Life Sciences,Peking University,Beijing,recently reported that
基金supported by National Natural Science Foundation of China (31921001)。
文摘Minichromosome Maintenance protein 10(MCM10)is essential for DNA replication initiation and DNA elongation in yeasts and animals.Although the functions of MCM10 in DNA replication and repair have been well documented,the detailed mechanisms for MCM10 in these processes are not well known.Here,we identified AtMCM10 gene through a forward genetic screening for releasing a silenced marker gene.Although plant MCM10 possesses a similar crystal structure as animal MCM10,AtMCM10 is not essential for plant growth or development in Arabidopsis.AtMCM10 can directly bind to histone H3-H4 and promotes nucleosome assembly in vitro.The nucleosome density is decreased in Atmcm10,and most of the nucleosome density decreased regions in Atmcm10 are also regulated by newly synthesized histone chaperone Chromatin Assembly Factor-1(CAF-1).Loss of both AtMCM10 and CAF-1 is embryo lethal,indicating that AtM CM10 and CAF-1 are indispensable for replication-coupled nucleosome assembly.AtMCM10 interacts with both new and parental histones.Atmcm10 mutants have lower H3.1abundance and reduced H3K27me1/3 levels with releasing some silenced transposons.We propose that AtM CM10 deposits new and parental histones during nucleosome assembly,maintaining proper epigenetic modifications and genome stability during DNA replication.
基金We thank Veder Garcia （University of California, Berkeley, USA） for critically reading the paper, Zengyong He for providing the AtFKBP53：：GUS transgenic line and Masami Horikoshi （The University of Tokyo, Japan） for the pET-6His-SpFkbp39P plasmid. This work was supported by grants from the National Science Foundation and US Department of Energy （toSL）.
文摘Chromatin structure is important for controlling gene expression, but mechanisms underlying chromatin remodel- ing are not fully understood. Here we report that an FKBP （FK506 binding protein） type immunophilin, AtFKBP53, possesses histone chaperone activity and is required for repressing ribosomal gene expression in Arabidopsis. The At- FKBP53 protein is a multidomain FKBP with a typical peptidylprolyl isomerase （PPIase） domain and several highly charged domains. Using nucleosome assembly assays, we showed that AtFKBP53 has histone chaperone activity and the charged acidic domains are sufficient for the activity. We show that AtFKBP53 interacts with histone H3 through the acidic domains, whereas the PPIase domain is dispensable for histone chaperone activity or histone binding. Ri- bosomal RNA gene （18S rDNA） is overexpressed when AtFKBP53 activity is reduced or eliminated in Arabidopsis plants. Chromatin immunoprecipitation assay showed that AtFKBP53 is associated with the 18S rDNA gene chro- matin, implicating that AtFKBP53 represses rRNA genes at the chromatin level. This study identifies a new histone chaperone in plants that functions in chromatin remodeling and regulation of transcription.
基金supported by the National Institutes of Health to R.B.D.(NIH5P30CA015083)the Mayo Clinic Cancer Center Ea-gles Cancer Fund(Z.W.)the Mayo Clinic Center for Biomedical Discovery(S.M.O).
文摘The long-term effectiveness of targeted cancer therapies is limited by the development of resistance.Although epigenetic reprogramming has been implicated in resistance,the mechanisms remain elusive.Herein,we demonstrate that increased chromatin accessibility is involved in adaptive BRAF inhibitor(BRAFi)-resistance in melanoma cells.We observed loss of chromatin assembly factor 1(CAF-1)and its related histone H3 lysine 9 trimethylation(H3K9me3)with adaptive BRAFi resistance.We further showed that depletion of CAF-1 provides chromatin plasticity for effective reprogramming by AP1 components to promote BRAFi resistance.Our data sug-gest that therapeutic approaches to restore H3K9me3 levels may compensate for the loss of CAF-1 and,in turn,suppress resistance to BRAF inhibitors.
