BACKGROUND Liver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually.Fibrosis develops from recurrent liver injury but the molecular mechanisms...BACKGROUND Liver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually.Fibrosis develops from recurrent liver injury but the molecular mechanisms are not fully understood.Recently,the TLR4-MyD88 signaling pathway has been reported to contribute to fibrosis.Extracellular histones are ligands of TLR4 but their roles in liver fibrosis have not been investigated.AIM To investigate the roles and potential mechanisms of extracellular histones in liver fibrosis.METHODS In vitro,LX2 human hepatic stellate cells(HSCs)were treated with histones in the presence or absence of non-anticoagulant heparin(NAHP)for neutralizing histones or TLR4-blocking antibody.The resultant cellular expression of collagen I was detected using western blotting and immunofluorescent staining.In vivo,the CCl4-induced liver fibrosis model was generated in male 6-week-old ICR mice and in TLR4 or MyD88 knockout and parental mice.Circulating histones were detected and the effect of NAHP was evaluated.RESULTS Extracellular histones strongly stimulated LX2 cells to produce collagen I.Histone-enhanced collagen expression was significantly reduced by NAHP and TLR4-blocking antibody.In CCl4-treated wild type mice,circulating histones were dramatically increased and maintained high levels during the duration of fibrosisinduction.Injection of NAHP not only reduced alanine aminotransferase and liver injury scores,but also significantly reduced fibrogenesis.Since the TLR4-blocking antibody reduced histone-enhanced collagen I production in HSC,the CCl4 model with TLR4 and MyD88 knockout mice was used to demonstrate the roles of the TLR4-MyD88 signaling pathway in CCl4-induced liver fibrosis.The levels of liver fibrosis were indeed significantly reduced in knockout mice compared to wild type parental mice.CONCLUSION Extracellular histones potentially enhance fibrogenesis via the TLR4–MyD88 signaling pathway and NAHP has therapeutic potential by detoxifying extracellular histones.展开更多
Linker histones, e.g., H1, are best known for their ability to bind to nucleosomes and stabilize both nucleosome structure and condensed higher-order chromatin structures. However, over the years many investigators ha...Linker histones, e.g., H1, are best known for their ability to bind to nucleosomes and stabilize both nucleosome structure and condensed higher-order chromatin structures. However, over the years many investigators have reported specific interactions between linker histones and proteins involved in important cellular processes. The purpose of this review is to highlight evidence indicating an important alternative mode of action for H1, namely protein-protein interactions. We first review key aspects of the traditional view of linker histone action, including the importance of the H1 C-terminal domain. We then discuss the current state of knowledge of linker histone interactions with other proteins, and, where possible, highlight the mechanism of linker histone-mediated protein-protein interactions. Taken together, the data suggest a combinatorial role for the linker histones, functioning both as primary chromatin architectural proteins and simultaneously as recruitment hubs for proteins involved in accessing and modifying the chromatin fiber.展开更多
Histone modifications are proposed to constitute a ＂histone code＂ for epigenetic regulation of gene expression. However, recent studies demonstrate that histones have to be disassembled from chromatin during transcr...Histone modifications are proposed to constitute a ＂histone code＂ for epigenetic regulation of gene expression. However, recent studies demonstrate that histones have to be disassembled from chromatin during transcription. Recent evidence, though not conclusive, suggests that histories might be degradable after being removed from chromatin during transcription. Degradation of overexpressed excessive histones, instead of native histones, has been shown to be dependent on proteasomes and ubiquitination. Since the 26S proteasome usually recognizes polyubiquitinated substrates, it is critical to demonstrate whether degradation of histones is mediated by polyubiquitination. Unexpectedly, there is almost no evidence that any ubiquitin ligase can promote polyubiquitination-dependent degradation of constitutive histones. Meanwhile, acetylation and phosphorylation are also associated with histone degradation. This review attempts to summarize the current knowledge on the transcription-coupled degradation of histones and its regulation by posttranslational protein modifications.展开更多
Oncohistones are histones with high-frequency point mutations that are associated with tumorigenesis. Although each histone variant is encoded by multiple genes, a single mutation in one allele of one gene seems to ha...Oncohistones are histones with high-frequency point mutations that are associated with tumorigenesis. Although each histone variant is encoded by multiple genes, a single mutation in one allele of one gene seems to have a dominant effect over global histone H3 methylation level at the relevant amino acid residue. These oncohistones are highly tumor type specific. For example, H3K27M and H3G34V/R mutations occur only in pediatric brain cancers, whereas H3K36M and H3G34W/L have only been found in pediatric bone tumors. H1 mutations also seem to be exclusively linked to lymphomas. In this review, we discuss the occurrence, frequency and potential functional mechanisms of each oncohistone in tumorigenesis of its relevant cancer. We believe that further investigation into the mechanism regarding their tumor type specificity and cancer-related functions will shed new light on their application in cancer diagnosis and targeted therapy development.展开更多
Using Brownian dynamics simulation, we studied the effect of histone modifications On conformations of an array of nucleosomes in a segment of chromatin. The simulation demonstrated that the segment of chromatin shows...Using Brownian dynamics simulation, we studied the effect of histone modifications On conformations of an array of nucleosomes in a segment of chromatin. The simulation demonstrated that the segment of chromatin shows the dynamic behaviour that its conformation can switch between a state with nearly all of the histones being wrapped by DNA and a state with nearly all of the histones being unwrapped by DNA, thus involving the ＂cross-talking＂ interactions among the histones. Each state can stay for a sufficiently long time. These conformational states are essential for gene expression or gene silence. The simulation also shows that these conformational states can be inherited by the daughter DNAs during DNA replication, giving a theoretical explanation of the epigenetic phenomenon.展开更多
The compaction of genomic DNA into nucleosomes with the help of histones has long been considered a fundamental feature exclusive to eukaryotic cells.However,it was recently shown that archaea and bacteria also encode...The compaction of genomic DNA into nucleosomes with the help of histones has long been considered a fundamental feature exclusive to eukaryotic cells.However,it was recently shown that archaea and bacteria also encode histones.A complex picture has emerged with more recent discoveries of eukaryotic-like histones within one phylum of doublestranded DNA(dsDNA)viruses.Nevertheless,the extent to which other dsDNA viruses encode histones remains largely unexplored.Here,we conducted a metagenomic survey of viral histones that were further clustered based on sequence and predicted structural similarities.We identified over 1500 viral histones and histone-fold proteins,including previously undescribed proteins found in the viral class Caudoviricetes.Structural predictions and in vitro assays demonstrated that histone triplets(where three histone folds are fused)and singlets co-occurring in the same viral genome are capable of forming nucleosome-like particles.Beyond nucleosomal histone functions,our analysis revealed six types of structurally and functionally diverse viral histone-fold proteins,some of which do not have known structural or functional homologs.Altogether,our findings reveal a previously unrecognized diversity of viral histones in dsDNA viruses,expanding the known repertoire,structural diversity,and functional versatility of viral histones beyond nucleocytoplasmic large DNA viruses.展开更多
Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expec...Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.展开更多
This article reviews the latest research developments in the field of eukaryotic gene regulation by the structural alterations of chromatin and nucleosomes. The following issues are briefly addressed: (i) nucleosome a...This article reviews the latest research developments in the field of eukaryotic gene regulation by the structural alterations of chromatin and nucleosomes. The following issues are briefly addressed: (i) nucleosome and histone modifications by both the ATP-dependent remodeling complexes and the histone acetyltransferases and their roles in gene activation; (ii) competitive binding of histones and transcription factors on gene promoters, and transcription repression by nucleosomes; and (iii) influences of linker histone HI on gene regulation. Meanwhile, the significance and impact of these new research progresses, as well as issues worthwhile for further study are commented.展开更多
Nanoparticle-based chemophotothermal therapy(CPT)is a promising treatment for multidrug resistant tumors.In this study,a drug nanococktail of DIR825@histone was developed by employing doxorubicin(DOX),NIR dye IR825 an...Nanoparticle-based chemophotothermal therapy(CPT)is a promising treatment for multidrug resistant tumors.In this study,a drug nanococktail of DIR825@histone was developed by employing doxorubicin(DOX),NIR dye IR825 and human histones for interventional nucleus-targeted CPT of multidrug resistant tumors with an interventional laser.After localized intervention,DIR825@histone penetrated tumor tissues by transcytosis,efficiently entered tumor cells and targeted the cell nuclei.DIR825@histone also exhibited good photothermal performance and thermal-triggered drug release.Efficient multidrug resistant tumor inhibition was achieved by enhanced CPT sensitization and MDR reversion via nuclear targeting.Moreover,an interventional laser assisted DIR825@histone in inhibiting multidrug resistant tumors by promoting the sufficient delivery of laser energy inside the tumor while reducing skin injury.Therefore,DIR825@histone together with this interventional nucleus-targeted CPT strategy holds great promise for treating multidrug resistant tumors.展开更多
The Jumonji C domain-containing(JmjC)histone demethylases(JMJs)are involved in various aspects of plant development and responses to environmental changes.AtJMJs have been extensively studied in Arabidopsis for their ...The Jumonji C domain-containing(JmjC)histone demethylases(JMJs)are involved in various aspects of plant development and responses to environmental changes.AtJMJs have been extensively studied in Arabidopsis for their roles in regulating flowering time,while their functions and molecular mechanisms in regulating flowering time in rice remain underexplored.Here,we demonstrate that the JmjC domain-only group member OsJMJ712 regulates heading date in rice.OsJMJ712 exhibits H3K36me3 demethylase activity at Ehd1 and RFT1 and represses the expression of Ehd1,Hd3a,and RFT1.Furthermore,loss of function of OsJMJ712 disrupts the circadian clock,and OsLHY directly binds to the promoter of OsJMJ712 to suppress its expression.These findings uncover that OsJMJ712 integrates histone demethylation and the circadian clock to fine-tune photoperiodic flowering in rice,providing new insights into the epigenetic control of photoperiodic flowering in crops.展开更多
Malignant melanoma(MM)is a highly aggressive skin cancer known for its rapid progression,potential for metastasis,and resistance to treatment.Despite advances in targeted therapies and immunotherapy,the prognosis for ...Malignant melanoma(MM)is a highly aggressive skin cancer known for its rapid progression,potential for metastasis,and resistance to treatment.Despite advances in targeted therapies and immunotherapy,the prognosis for metastatic melanoma remains unfavorable.Recent research has shed light on the significance of epigenetic modifications in the pathogenesis of melanoma,revealing critical mechanisms of melanoma development and progression.Epigenetic modifications,including DNA and RNA modifications,histone modifications,chromatin remodeling,and non-coding RNA regulation,disrupt normal gene expression without modifying the DNA sequence,leading to cellular transformation,invasion,immune evasion,and therapeutic resistance.The reversible nature of epigenetic modifications opens up new opportunities for melanoma recognition and classification,as well as therapeutic applications,including the development of diagnostic and prognostic biomarkers and innovative targeted therapies aimed at restoring normal gene function and enhancing the efficacy of existing treatments.This review will focus on the multifaceted role of epigenetic dysregulation in melanoma.The future integration of epigenetic data and genomic profiling with clinical outcomes,likely facilitated by artificial intelligence(AI)algorithms,holds promise for personalized treatment strategies that are informed by precise and combinatorial diagnostic tools,ultimately improving melanoma care.The study aims to deliver a comprehensive overview of the current state of epigenetics in melanoma.展开更多
Background As a unique livestock adapted to the harsh environment,grazing yaks frequently suffer from malnutrition and even death because of the lower yield and quality of forage in the Qinghai-Tibet Plateau during th...Background As a unique livestock adapted to the harsh environment,grazing yaks frequently suffer from malnutrition and even death because of the lower yield and quality of forage in the Qinghai-Tibet Plateau during the cold season.Certain stress conditions,such as environmental changes,disease,and malnutrition,can lead to a decrease in glutamine(Gln)synthesis,which fails to cover the physiological needs of the organism.Supplementation with exogenous Gln can promote nutrient digestion and improve rumen fermentation in ruminant animals under malnutrition.However,whether Gln could alleviate the barrier function injury induced by malnutrition and its mechanism is still unclear.Methods In the in vivo experiments,24 healthy yaks(31 months,265.35±25.81 kg)were randomly divided into 3 groups,namely control group(Con,free access to the basal diet),feed restriction group(FR,50% level of ad libitum feed intake),and feed restriction+Gln group(FR+Gln,50% level of ad libitum feed intake from d 1 to 30,50% level of ad libitum feed intake+1%Gln from d 31 to 60).In the in vitro experiments,the yak rumen epithelial cells(YRECs)were divided into 4 groups:Con group(complete medium),Gln group(complete medium+10 mmol/L Gln),Gln deficiency group(Gln-D,Gln-free medium),and Gln deficiency+Gln group(Gln-D+Gln,Gln-free medium+10 mmol/L Gln).Results In the in vivo experiments,FR significantly decreased the ruminal concentrations of acetate,propionate,butyrate,iso-butyrate,and total volatile fatty acid(VFA)(P<0.05).FR also reduced the m RNA expression of NHE1,Na^(+)/K^(+)-ATPase,and Ca^(2+)/Mg^(2+)-ATPase,and the concentrations of lactate,histone acetyltransferase(p300),histone deacetylase(HDAC),as well as the histone lysine lactylation level compared to Con group,while Gln supplementation alleviated them(P<0.05).In the in vitro experiments,Gln alleviated the Gln-D-induced down-regulation of NHE1,Na^(+)/K^(+)-ATPase,and Ca^(2+)/Mg^(2+)-ATPase m RNA expressions and reduction of lactate,p300,HDAC concentrations,and histone lysine lactylation level(P<0.05).Besides,p300 inhibitor abrogated Gln repair of barrier function damage in YRECs(P<0.05).Conclusions Overall,our results revealed the potential mechanism of Gln supplementation to repair malnutritioninduced damage of rumen epithelial barrier function in yaks,which might be related to histone lysine lactylation.However,because we do not have a control group receiving glutamine alone,we cannot determine the impact of Gln on the rumen epithelial function of normal yaks.展开更多
Cognitive impairment is a complex neurodegenerative disorder,and increased homocysteine levels are recognized as a major risk factor for this condition.Epigenetic modifications,particularly histone acetylation,have be...Cognitive impairment is a complex neurodegenerative disorder,and increased homocysteine levels are recognized as a major risk factor for this condition.Epigenetic modifications,particularly histone acetylation,have been implicated in the progression of cognitive impairment;however,the mechanisms underlying hyperhomocysteinemia-induced cognitive impairment remain unclear.In this study,we developed an hyperhomocysteinemia-induced cognitive impairment model by feeding mice a high-methionine diet and conducted behavioral and molecular analyses to elucidate the mechanisms involved in cognitive impairment.Behavioral experiments revealed significant cognitive deficits and neuroinflammation accompanied by a marked decrease in histone H3 lysine 27 acetylation in the hippocampus and cortex.Furthermore,metabolomic profiling and chromatin immunoprecipitation sequencing demonstrated substantial shifts in the levels of homocysteine metabolites and identified histone H3 lysine 27 acetylation-targeted genes involved in synaptic long-term potentiation,including Gria1,Gria3,Grin2a,Grin2b,Slc1a1,Slc24a2,Ptk2b,and Src.RNA sequencing confirmed that hyperhomocysteinemia induced neurodegeneration.In vitro experiments confirmed that decreased histone H3 lysine 27 acetylation downregulates the expression of these target genes in homocysteine-treated HT-22 cells,thereby impairing synaptic plasticity.Collectively,these findings suggest that aberrant expression of long-term potentiation-related genes regulated by histone H3 lysine 27 acetylation is a key driver of hyperhomocysteinemia-induced cognitive impairment.Targeting histone H3 lysine 27 acetylation-mediated epigenetic dysregulation may be a promising therapeutic strategy,offering potential avenues for intervention in individuals with cognitive impairment and neurodegenerative disorders.展开更多
Plants deploy a two-layered immune system:pathogen-associated molecular pattern(PAMP)-triggered immunity(PTl)and effector-triggered immunity(ETI).While PTI is initiated by cell surface receptors,ETI relies on intracel...Plants deploy a two-layered immune system:pathogen-associated molecular pattern(PAMP)-triggered immunity(PTl)and effector-triggered immunity(ETI).While PTI is initiated by cell surface receptors,ETI relies on intracellular NLR receptors that recognize pathogen effectors(Jones et al.,2024).The nucleoporin CONSTITUTIVE EXPRESSER OF PATHOGENESIS-RELATED GENES 5(CPR5)is a key negative regulator of ETI.CPR5 integrates nuclear transport,cell cycle control,and RNA processing to suppress immune signaling(Wang et al.,2014;Gu et al.,2016;Peng et al.,2022).Recent work revealed that CPR5 also modulates immunity through another nucleoporin,GUANYLATE-BINDING PROTEIN-LIKE 3(GBPL3),which interaCtS with PWWP-DOMAIN INTERACTOR OF POLYCOMBS1(PWO1),a key component of the chromatin-associated methyltransferase POLYCOMB REPRESSIVE COMPLEX 2(PRC2)(Reimann et al.,2023;Pan et al.,2025).These findings suggest unexplored roles for chromatin remodeling in the CPR5-mediated immunity.展开更多
Ischemic retinopathy is a leading cause of blindness:Ischemic retinopathies including diabetic retinopathy(DR),retinopathy of prematurity,and retinal artery and vein occlusion are major causes of visual impairment.Isc...Ischemic retinopathy is a leading cause of blindness:Ischemic retinopathies including diabetic retinopathy(DR),retinopathy of prematurity,and retinal artery and vein occlusion are major causes of visual impairment.Ischemic retinopathy can be acute,such as in central or branch retinal artery occlusion,or chronic,such as with DR(Figure 1).Although the causes of retinopathies are diverse,one pathogenic event shared by these conditions is the myeloid cell response to retinal ischemia(Shahror et al.,2024a).展开更多
Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein ...Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.展开更多
Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of...Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of interferon regulatory factor 1 in myasthenia gravis,with an aim to understand the underlying mechanisms.Patients with myasthenia gravis who had acetylcholine receptor antibodies were included in the study.Peripheral blood lymphocytes were extracted from the included patients,and B lymphocyte subsets were isolated.Next,T and B cells from peripheral blood were co-cultured to explore the interferon regulatory factor 1-related mechanisms in myasthenia gravis.Chromatin immunoprecipitation experiments confirmed an interaction between interferon regulatory factor 1 and the CD180 promoter region.Dual-luciferase reporter gene confirmed the transcriptional activity of interferon regulatory factor 1 on CD180 promoter.In vitro results further indicated that interferon regulatory factor 1 promoted B cell activation and T cell differentiation via the inhibition of CD180.Interferon regulatory factor 1 recruited histone deacetylase 1 to inhibit CD180 transcription.Additionally,histone deacetylase 1 promoted B cell activation and T cell differentiation.Finally,in vitro experiments demonstrated that CD180 inhibited B cell activation and T cell differentiation by inhibiting the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Collectively,our results suggest that interferon regulatory factor 1 enhances T cell differentiation by recruiting histone deacetylase 1 to block B cell CD180 transcription in myasthenia gravis via the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Together,these findings indicate the important role of interferon regulatory factor 1 in myasthenia gravis and suggest its molecular mechanisms.They also provide new ideas and targets for diagnosing and treating myasthenia gravis,which will be both scientifically and clinically valuable.展开更多
The anticancer therapies with the joint treatment of a histone deacetylase(HDAC) inhibitor and a DNA-damaging approach are actively under clinical investigations, but the underlying mechanism is unclear. Histone homeo...The anticancer therapies with the joint treatment of a histone deacetylase(HDAC) inhibitor and a DNA-damaging approach are actively under clinical investigations, but the underlying mechanism is unclear. Histone homeostasis is critical to genome stability, transcriptional accuracy, DNA repair process, senescence, and survival. We have previously demonstrated that the HDAC inhibitor, trichostatin A(TSA), could promote the degradation of the core histones induced by γ-radiation or the DNAalkylating agent methyl methanesulfonate(MMS) in non-cancer cells, including mouse spermatocyte and embryonic fibroblast cell lines. In this study, we found that the joint treatment by TSA and MMS induced the death of the cultured cancer cells with an additive effect, but induced degradation of the core histones synergistically in these cells. We then analyzed various combinations of other HDAC inhibitors, including suberoylanilide hydroxamic acid and valproate sodium, with MMS or other DNAdamaging agents, including etoposide and camptothecin. Most of these combined treatments induced cell death additively, but all the tested combinations induced degradation of the core histones synergistically. Meanwhile, we showed that cell cycle arrest might not be a primary consequence for the joint treatment of TSA and MMS. Given that clinic treatments of cancers jointly with an HDAC inhibitor and a DNA-damaging approach often show synergistic effects, histone degradation might more accurately underlie the synergistic effects of these joint treatments in clinic applications than other parameters, such as cell death and cell cycle arrest. Thus, our studies might suggest that the degradation of the core histones can serve as a new target for the development of cancer therapies.展开更多
Histones package DNA in all eukaryotes and play key roles in regulating gene expression. Approximately 150 base pairs of DNA wraps around an octamer of core histones to form the nucleosome, the basic unit of chromatin...Histones package DNA in all eukaryotes and play key roles in regulating gene expression. Approximately 150 base pairs of DNA wraps around an octamer of core histones to form the nucleosome, the basic unit of chromatin. Linker histones compact chromatin further by binding to and neutralizing the charge of the DNA between nucleosomes. It is well established that chromatin packing is regulated by a complex pattern of posttranslational modifications （PTMs） to core histones, but linker histone function is less well understood. In this review, we describe the current understand- ing of the many roles that linker histones play in cellular processes, including gene regulation, cell division, and devel- opment, while putting the linker histone in the context of other nuclear proteins. Although intriguing roles for plant linker histones are beginning to emerge, much of our current understanding comes from work in animal systems. Many unanswered questions remain and additional work is required to fully elucidate the complex processes mediated by linker histones in plants.展开更多
UV differential spectroscopy, fluorescence spectroscopy and circular dichroism (CD) spectroscopy assays have been applied to studying the conformation alteration of mouse hepatic histones H1 and H3 after reacting with...UV differential spectroscopy, fluorescence spectroscopy and circular dichroism (CD) spectroscopy assays have been applied to studying the conformation alteration of mouse hepatic histones H1 and H3 after reacting with nicotine in vitro. The results indicate that their conformation changes from regular form to random form with the increasing reaction dose of nicotine. The adduction of nicotine or its metabolites with histones H1 and H3 accounts for the conformation alteration. Nicotine may affect the structure, function and expression of genes of chromosome by changing the conformation of histones.展开更多
基金Supported by Key R&D Program of Jiangsu Province,No.BE2019712British Heart Foundation,No.PG/14/19/30751 and No.PG/16/65/32313.
文摘BACKGROUND Liver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually.Fibrosis develops from recurrent liver injury but the molecular mechanisms are not fully understood.Recently,the TLR4-MyD88 signaling pathway has been reported to contribute to fibrosis.Extracellular histones are ligands of TLR4 but their roles in liver fibrosis have not been investigated.AIM To investigate the roles and potential mechanisms of extracellular histones in liver fibrosis.METHODS In vitro,LX2 human hepatic stellate cells(HSCs)were treated with histones in the presence or absence of non-anticoagulant heparin(NAHP)for neutralizing histones or TLR4-blocking antibody.The resultant cellular expression of collagen I was detected using western blotting and immunofluorescent staining.In vivo,the CCl4-induced liver fibrosis model was generated in male 6-week-old ICR mice and in TLR4 or MyD88 knockout and parental mice.Circulating histones were detected and the effect of NAHP was evaluated.RESULTS Extracellular histones strongly stimulated LX2 cells to produce collagen I.Histone-enhanced collagen expression was significantly reduced by NAHP and TLR4-blocking antibody.In CCl4-treated wild type mice,circulating histones were dramatically increased and maintained high levels during the duration of fibrosisinduction.Injection of NAHP not only reduced alanine aminotransferase and liver injury scores,but also significantly reduced fibrogenesis.Since the TLR4-blocking antibody reduced histone-enhanced collagen I production in HSC,the CCl4 model with TLR4 and MyD88 knockout mice was used to demonstrate the roles of the TLR4-MyD88 signaling pathway in CCl4-induced liver fibrosis.The levels of liver fibrosis were indeed significantly reduced in knockout mice compared to wild type parental mice.CONCLUSION Extracellular histones potentially enhance fibrogenesis via the TLR4–MyD88 signaling pathway and NAHP has therapeutic potential by detoxifying extracellular histones.
文摘Linker histones, e.g., H1, are best known for their ability to bind to nucleosomes and stabilize both nucleosome structure and condensed higher-order chromatin structures. However, over the years many investigators have reported specific interactions between linker histones and proteins involved in important cellular processes. The purpose of this review is to highlight evidence indicating an important alternative mode of action for H1, namely protein-protein interactions. We first review key aspects of the traditional view of linker histone action, including the importance of the H1 C-terminal domain. We then discuss the current state of knowledge of linker histone interactions with other proteins, and, where possible, highlight the mechanism of linker histone-mediated protein-protein interactions. Taken together, the data suggest a combinatorial role for the linker histones, functioning both as primary chromatin architectural proteins and simultaneously as recruitment hubs for proteins involved in accessing and modifying the chromatin fiber.
基金supported by grants from the Ministry of Science and Technology of China (No.2012CB910300)the National Natural Science Foundation of China(No.30525033)the Fundamental Research Funds for the Central Universities of China to X.-B.O
文摘Histone modifications are proposed to constitute a ＂histone code＂ for epigenetic regulation of gene expression. However, recent studies demonstrate that histones have to be disassembled from chromatin during transcription. Recent evidence, though not conclusive, suggests that histories might be degradable after being removed from chromatin during transcription. Degradation of overexpressed excessive histones, instead of native histones, has been shown to be dependent on proteasomes and ubiquitination. Since the 26S proteasome usually recognizes polyubiquitinated substrates, it is critical to demonstrate whether degradation of histones is mediated by polyubiquitination. Unexpectedly, there is almost no evidence that any ubiquitin ligase can promote polyubiquitination-dependent degradation of constitutive histones. Meanwhile, acetylation and phosphorylation are also associated with histone degradation. This review attempts to summarize the current knowledge on the transcription-coupled degradation of histones and its regulation by posttranslational protein modifications.
基金supported by the Chinese National Natural Science Foundation Projects (No. 81672782)
文摘Oncohistones are histones with high-frequency point mutations that are associated with tumorigenesis. Although each histone variant is encoded by multiple genes, a single mutation in one allele of one gene seems to have a dominant effect over global histone H3 methylation level at the relevant amino acid residue. These oncohistones are highly tumor type specific. For example, H3K27M and H3G34V/R mutations occur only in pediatric brain cancers, whereas H3K36M and H3G34W/L have only been found in pediatric bone tumors. H1 mutations also seem to be exclusively linked to lymphomas. In this review, we discuss the occurrence, frequency and potential functional mechanisms of each oncohistone in tumorigenesis of its relevant cancer. We believe that further investigation into the mechanism regarding their tumor type specificity and cancer-related functions will shed new light on their application in cancer diagnosis and targeted therapy development.
基金Project supported by the National Natural Science Foundation of China (Grants Nos. 10834014 and 10674173)the National Basic Research Program of China (Grant No. 2009CB930704)
文摘Using Brownian dynamics simulation, we studied the effect of histone modifications On conformations of an array of nucleosomes in a segment of chromatin. The simulation demonstrated that the segment of chromatin shows the dynamic behaviour that its conformation can switch between a state with nearly all of the histones being wrapped by DNA and a state with nearly all of the histones being unwrapped by DNA, thus involving the ＂cross-talking＂ interactions among the histones. Each state can stay for a sufficiently long time. These conformational states are essential for gene expression or gene silence. The simulation also shows that these conformational states can be inherited by the daughter DNAs during DNA replication, giving a theoretical explanation of the epigenetic phenomenon.
基金funded by the National Key Research and Development Program of China(2023YFC2306800 to Yue Liu)the National Natural Science Foundation of China(82188102 to HaiboWang)the EuropeanMolecularBiology Organization Scientific Exchange Grant(10347 to Yang Liu).
文摘The compaction of genomic DNA into nucleosomes with the help of histones has long been considered a fundamental feature exclusive to eukaryotic cells.However,it was recently shown that archaea and bacteria also encode histones.A complex picture has emerged with more recent discoveries of eukaryotic-like histones within one phylum of doublestranded DNA(dsDNA)viruses.Nevertheless,the extent to which other dsDNA viruses encode histones remains largely unexplored.Here,we conducted a metagenomic survey of viral histones that were further clustered based on sequence and predicted structural similarities.We identified over 1500 viral histones and histone-fold proteins,including previously undescribed proteins found in the viral class Caudoviricetes.Structural predictions and in vitro assays demonstrated that histone triplets(where three histone folds are fused)and singlets co-occurring in the same viral genome are capable of forming nucleosome-like particles.Beyond nucleosomal histone functions,our analysis revealed six types of structurally and functionally diverse viral histone-fold proteins,some of which do not have known structural or functional homologs.Altogether,our findings reveal a previously unrecognized diversity of viral histones in dsDNA viruses,expanding the known repertoire,structural diversity,and functional versatility of viral histones beyond nucleocytoplasmic large DNA viruses.
基金supported by the National Science Foundation for Excellent Young Scholars (32122052)National Natural Science Foundation Regional Innovation and Development (No.U19A2003).
文摘Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.
基金Part of the work in this article was supported by the National Natural Science Foundation of China (Grant No. 3997038) and the National "973" Basic Research Project (Grant No. G19I99053902).
文摘This article reviews the latest research developments in the field of eukaryotic gene regulation by the structural alterations of chromatin and nucleosomes. The following issues are briefly addressed: (i) nucleosome and histone modifications by both the ATP-dependent remodeling complexes and the histone acetyltransferases and their roles in gene activation; (ii) competitive binding of histones and transcription factors on gene promoters, and transcription repression by nucleosomes; and (iii) influences of linker histone HI on gene regulation. Meanwhile, the significance and impact of these new research progresses, as well as issues worthwhile for further study are commented.
基金This work was financially supported by National Natural Science Foundation of China(No.81701822)Heilongjiang Province Science Foundation for Youths(No.QC2018090)+3 种基金the Fundamental Research Funds for Central Universities(No.2572017PZ09)China Postdoctoral Science Foundation(No.2016M600238)Heilongjiang Postdoctoral Special Fund(No.LBH-TZ1601)Northeast Forestry University Double First-Rate Construction Fund(No.000/41113281).
文摘Nanoparticle-based chemophotothermal therapy(CPT)is a promising treatment for multidrug resistant tumors.In this study,a drug nanococktail of DIR825@histone was developed by employing doxorubicin(DOX),NIR dye IR825 and human histones for interventional nucleus-targeted CPT of multidrug resistant tumors with an interventional laser.After localized intervention,DIR825@histone penetrated tumor tissues by transcytosis,efficiently entered tumor cells and targeted the cell nuclei.DIR825@histone also exhibited good photothermal performance and thermal-triggered drug release.Efficient multidrug resistant tumor inhibition was achieved by enhanced CPT sensitization and MDR reversion via nuclear targeting.Moreover,an interventional laser assisted DIR825@histone in inhibiting multidrug resistant tumors by promoting the sufficient delivery of laser energy inside the tumor while reducing skin injury.Therefore,DIR825@histone together with this interventional nucleus-targeted CPT strategy holds great promise for treating multidrug resistant tumors.
基金funded by the Zhejiang Zhengjingyuan Pharmacy Chain Co.,Ltd.,China(Grant No.2025-KYY-516030-0001).
文摘The Jumonji C domain-containing(JmjC)histone demethylases(JMJs)are involved in various aspects of plant development and responses to environmental changes.AtJMJs have been extensively studied in Arabidopsis for their roles in regulating flowering time,while their functions and molecular mechanisms in regulating flowering time in rice remain underexplored.Here,we demonstrate that the JmjC domain-only group member OsJMJ712 regulates heading date in rice.OsJMJ712 exhibits H3K36me3 demethylase activity at Ehd1 and RFT1 and represses the expression of Ehd1,Hd3a,and RFT1.Furthermore,loss of function of OsJMJ712 disrupts the circadian clock,and OsLHY directly binds to the promoter of OsJMJ712 to suppress its expression.These findings uncover that OsJMJ712 integrates histone demethylation and the circadian clock to fine-tune photoperiodic flowering in rice,providing new insights into the epigenetic control of photoperiodic flowering in crops.
文摘Malignant melanoma(MM)is a highly aggressive skin cancer known for its rapid progression,potential for metastasis,and resistance to treatment.Despite advances in targeted therapies and immunotherapy,the prognosis for metastatic melanoma remains unfavorable.Recent research has shed light on the significance of epigenetic modifications in the pathogenesis of melanoma,revealing critical mechanisms of melanoma development and progression.Epigenetic modifications,including DNA and RNA modifications,histone modifications,chromatin remodeling,and non-coding RNA regulation,disrupt normal gene expression without modifying the DNA sequence,leading to cellular transformation,invasion,immune evasion,and therapeutic resistance.The reversible nature of epigenetic modifications opens up new opportunities for melanoma recognition and classification,as well as therapeutic applications,including the development of diagnostic and prognostic biomarkers and innovative targeted therapies aimed at restoring normal gene function and enhancing the efficacy of existing treatments.This review will focus on the multifaceted role of epigenetic dysregulation in melanoma.The future integration of epigenetic data and genomic profiling with clinical outcomes,likely facilitated by artificial intelligence(AI)algorithms,holds promise for personalized treatment strategies that are informed by precise and combinatorial diagnostic tools,ultimately improving melanoma care.The study aims to deliver a comprehensive overview of the current state of epigenetics in melanoma.
基金the National Natural Science Foundation of China(NSFC),Grant/Award Number:32272909Discipline Construction Program in Sichuan Agricultural University(2221993012)China Agriculture(Beef Cattle/Yak)Research System of MOF and MARA(CARS-37)。
文摘Background As a unique livestock adapted to the harsh environment,grazing yaks frequently suffer from malnutrition and even death because of the lower yield and quality of forage in the Qinghai-Tibet Plateau during the cold season.Certain stress conditions,such as environmental changes,disease,and malnutrition,can lead to a decrease in glutamine(Gln)synthesis,which fails to cover the physiological needs of the organism.Supplementation with exogenous Gln can promote nutrient digestion and improve rumen fermentation in ruminant animals under malnutrition.However,whether Gln could alleviate the barrier function injury induced by malnutrition and its mechanism is still unclear.Methods In the in vivo experiments,24 healthy yaks(31 months,265.35±25.81 kg)were randomly divided into 3 groups,namely control group(Con,free access to the basal diet),feed restriction group(FR,50% level of ad libitum feed intake),and feed restriction+Gln group(FR+Gln,50% level of ad libitum feed intake from d 1 to 30,50% level of ad libitum feed intake+1%Gln from d 31 to 60).In the in vitro experiments,the yak rumen epithelial cells(YRECs)were divided into 4 groups:Con group(complete medium),Gln group(complete medium+10 mmol/L Gln),Gln deficiency group(Gln-D,Gln-free medium),and Gln deficiency+Gln group(Gln-D+Gln,Gln-free medium+10 mmol/L Gln).Results In the in vivo experiments,FR significantly decreased the ruminal concentrations of acetate,propionate,butyrate,iso-butyrate,and total volatile fatty acid(VFA)(P<0.05).FR also reduced the m RNA expression of NHE1,Na^(+)/K^(+)-ATPase,and Ca^(2+)/Mg^(2+)-ATPase,and the concentrations of lactate,histone acetyltransferase(p300),histone deacetylase(HDAC),as well as the histone lysine lactylation level compared to Con group,while Gln supplementation alleviated them(P<0.05).In the in vitro experiments,Gln alleviated the Gln-D-induced down-regulation of NHE1,Na^(+)/K^(+)-ATPase,and Ca^(2+)/Mg^(2+)-ATPase m RNA expressions and reduction of lactate,p300,HDAC concentrations,and histone lysine lactylation level(P<0.05).Besides,p300 inhibitor abrogated Gln repair of barrier function damage in YRECs(P<0.05).Conclusions Overall,our results revealed the potential mechanism of Gln supplementation to repair malnutritioninduced damage of rumen epithelial barrier function in yaks,which might be related to histone lysine lactylation.However,because we do not have a control group receiving glutamine alone,we cannot determine the impact of Gln on the rumen epithelial function of normal yaks.
基金supported by the Science Research Start-up Fund for Doctor of Shanxi Medical University,No.SD2114(to JL).
文摘Cognitive impairment is a complex neurodegenerative disorder,and increased homocysteine levels are recognized as a major risk factor for this condition.Epigenetic modifications,particularly histone acetylation,have been implicated in the progression of cognitive impairment;however,the mechanisms underlying hyperhomocysteinemia-induced cognitive impairment remain unclear.In this study,we developed an hyperhomocysteinemia-induced cognitive impairment model by feeding mice a high-methionine diet and conducted behavioral and molecular analyses to elucidate the mechanisms involved in cognitive impairment.Behavioral experiments revealed significant cognitive deficits and neuroinflammation accompanied by a marked decrease in histone H3 lysine 27 acetylation in the hippocampus and cortex.Furthermore,metabolomic profiling and chromatin immunoprecipitation sequencing demonstrated substantial shifts in the levels of homocysteine metabolites and identified histone H3 lysine 27 acetylation-targeted genes involved in synaptic long-term potentiation,including Gria1,Gria3,Grin2a,Grin2b,Slc1a1,Slc24a2,Ptk2b,and Src.RNA sequencing confirmed that hyperhomocysteinemia induced neurodegeneration.In vitro experiments confirmed that decreased histone H3 lysine 27 acetylation downregulates the expression of these target genes in homocysteine-treated HT-22 cells,thereby impairing synaptic plasticity.Collectively,these findings suggest that aberrant expression of long-term potentiation-related genes regulated by histone H3 lysine 27 acetylation is a key driver of hyperhomocysteinemia-induced cognitive impairment.Targeting histone H3 lysine 27 acetylation-mediated epigenetic dysregulation may be a promising therapeutic strategy,offering potential avenues for intervention in individuals with cognitive impairment and neurodegenerative disorders.
基金supported by grants from the National Natural Science Foundation of China(32270290)the Shanghai Engineering Research Center of Plant Germplasm Resources(17DZ2252700).
文摘Plants deploy a two-layered immune system:pathogen-associated molecular pattern(PAMP)-triggered immunity(PTl)and effector-triggered immunity(ETI).While PTI is initiated by cell surface receptors,ETI relies on intracellular NLR receptors that recognize pathogen effectors(Jones et al.,2024).The nucleoporin CONSTITUTIVE EXPRESSER OF PATHOGENESIS-RELATED GENES 5(CPR5)is a key negative regulator of ETI.CPR5 integrates nuclear transport,cell cycle control,and RNA processing to suppress immune signaling(Wang et al.,2014;Gu et al.,2016;Peng et al.,2022).Recent work revealed that CPR5 also modulates immunity through another nucleoporin,GUANYLATE-BINDING PROTEIN-LIKE 3(GBPL3),which interaCtS with PWWP-DOMAIN INTERACTOR OF POLYCOMBS1(PWO1),a key component of the chromatin-associated methyltransferase POLYCOMB REPRESSIVE COMPLEX 2(PRC2)(Reimann et al.,2023;Pan et al.,2025).These findings suggest unexplored roles for chromatin remodeling in the CPR5-mediated immunity.
基金supported by the National Institute of Health/National Eye Institute(NIH/NEI)grants(R00 EY029373,R01 EY035658)to AYFKnights Templar Eye Foundation Research Grant to ESIntramural UAMS Hornick and Sturgis grants to AYF and ES respectively。
文摘Ischemic retinopathy is a leading cause of blindness:Ischemic retinopathies including diabetic retinopathy(DR),retinopathy of prematurity,and retinal artery and vein occlusion are major causes of visual impairment.Ischemic retinopathy can be acute,such as in central or branch retinal artery occlusion,or chronic,such as with DR(Figure 1).Although the causes of retinopathies are diverse,one pathogenic event shared by these conditions is the myeloid cell response to retinal ischemia(Shahror et al.,2024a).
基金supported by Applied Basic Research Joint Fund Project of Yunnan Province,No.202301AY070001-200Middle-aged Academic and Technical Training Project for High-Level Talents,No.202105AC160065+1 种基金Yunnan Clinical Medical Center for Neurological and Cardiovascular Diseases,No.YWLCYXZX2023300077Key Clinical Specialty of Neurology in Yunnan Province,No.300064(all to CL)。
文摘Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.
基金National Natural Science Foundation of China,No.82271440Jiangxi Provincial Health Technology Project,No.202510009(both to LX).
文摘Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis.However,its function in myasthenia gravis remains unclear.Herein,we explored the function of interferon regulatory factor 1 in myasthenia gravis,with an aim to understand the underlying mechanisms.Patients with myasthenia gravis who had acetylcholine receptor antibodies were included in the study.Peripheral blood lymphocytes were extracted from the included patients,and B lymphocyte subsets were isolated.Next,T and B cells from peripheral blood were co-cultured to explore the interferon regulatory factor 1-related mechanisms in myasthenia gravis.Chromatin immunoprecipitation experiments confirmed an interaction between interferon regulatory factor 1 and the CD180 promoter region.Dual-luciferase reporter gene confirmed the transcriptional activity of interferon regulatory factor 1 on CD180 promoter.In vitro results further indicated that interferon regulatory factor 1 promoted B cell activation and T cell differentiation via the inhibition of CD180.Interferon regulatory factor 1 recruited histone deacetylase 1 to inhibit CD180 transcription.Additionally,histone deacetylase 1 promoted B cell activation and T cell differentiation.Finally,in vitro experiments demonstrated that CD180 inhibited B cell activation and T cell differentiation by inhibiting the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Collectively,our results suggest that interferon regulatory factor 1 enhances T cell differentiation by recruiting histone deacetylase 1 to block B cell CD180 transcription in myasthenia gravis via the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway.Together,these findings indicate the important role of interferon regulatory factor 1 in myasthenia gravis and suggest its molecular mechanisms.They also provide new ideas and targets for diagnosing and treating myasthenia gravis,which will be both scientifically and clinically valuable.
基金supported by the National Natural Science Foundation of China (31530014, 91319303 & 31600626)
文摘The anticancer therapies with the joint treatment of a histone deacetylase(HDAC) inhibitor and a DNA-damaging approach are actively under clinical investigations, but the underlying mechanism is unclear. Histone homeostasis is critical to genome stability, transcriptional accuracy, DNA repair process, senescence, and survival. We have previously demonstrated that the HDAC inhibitor, trichostatin A(TSA), could promote the degradation of the core histones induced by γ-radiation or the DNAalkylating agent methyl methanesulfonate(MMS) in non-cancer cells, including mouse spermatocyte and embryonic fibroblast cell lines. In this study, we found that the joint treatment by TSA and MMS induced the death of the cultured cancer cells with an additive effect, but induced degradation of the core histones synergistically in these cells. We then analyzed various combinations of other HDAC inhibitors, including suberoylanilide hydroxamic acid and valproate sodium, with MMS or other DNAdamaging agents, including etoposide and camptothecin. Most of these combined treatments induced cell death additively, but all the tested combinations induced degradation of the core histones synergistically. Meanwhile, we showed that cell cycle arrest might not be a primary consequence for the joint treatment of TSA and MMS. Given that clinic treatments of cancers jointly with an HDAC inhibitor and a DNA-damaging approach often show synergistic effects, histone degradation might more accurately underlie the synergistic effects of these joint treatments in clinic applications than other parameters, such as cell death and cell cycle arrest. Thus, our studies might suggest that the degradation of the core histones can serve as a new target for the development of cancer therapies.
文摘Histones package DNA in all eukaryotes and play key roles in regulating gene expression. Approximately 150 base pairs of DNA wraps around an octamer of core histones to form the nucleosome, the basic unit of chromatin. Linker histones compact chromatin further by binding to and neutralizing the charge of the DNA between nucleosomes. It is well established that chromatin packing is regulated by a complex pattern of posttranslational modifications （PTMs） to core histones, but linker histone function is less well understood. In this review, we describe the current understand- ing of the many roles that linker histones play in cellular processes, including gene regulation, cell division, and devel- opment, while putting the linker histone in the context of other nuclear proteins. Although intriguing roles for plant linker histones are beginning to emerge, much of our current understanding comes from work in animal systems. Many unanswered questions remain and additional work is required to fully elucidate the complex processes mediated by linker histones in plants.
文摘UV differential spectroscopy, fluorescence spectroscopy and circular dichroism (CD) spectroscopy assays have been applied to studying the conformation alteration of mouse hepatic histones H1 and H3 after reacting with nicotine in vitro. The results indicate that their conformation changes from regular form to random form with the increasing reaction dose of nicotine. The adduction of nicotine or its metabolites with histones H1 and H3 accounts for the conformation alteration. Nicotine may affect the structure, function and expression of genes of chromosome by changing the conformation of histones.
