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
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
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
Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of pro...Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of proteins,which in turn regulates cellular metabolism,aging,and the onset of disease.This review classifies proteins with lactylation effects into histones and non-histone proteins and analyzes their functional roles when lactylation occurs.The in-depth exploration of lactylation is still in its infancy,and many aspects of its regulation,functional significance and therapeutic potential need to be further explored.展开更多
Objective To investigate the treatment effect of the histone demethylase inhibitor GSK-J4,a small molecule that inhibits the demethylase activity of Jumonji domain-containing protein 3(JMJD3),in the treatment of perio...Objective To investigate the treatment effect of the histone demethylase inhibitor GSK-J4,a small molecule that inhibits the demethylase activity of Jumonji domain-containing protein 3(JMJD3),in the treatment of periodontitis.Methods Gingival tissues from patients with moderate to severe chronic periodontitis and healthy controls were collected to evaluate JMJD3 expression via real-time quantitative reverse transcription PCR(RT-qPCR)and immunohistochemistry(IHC).Next,Sprague–Dawley(SD)rats were used to investigate the effect of GSK-J4 in vivo.The experimental periodontitis model was induced by upper first molar ligation and gingival sulcus injection of Porphyromonas gingivalis.The rats were divided into a healthy group,a periodontitis group,periodontitis plus GSK-J4 treatment groups(P+GSK-J415 mg/kg or 25 mg/kg),and a periodontitis plus dimethyl sulfoxide(DMSO)group(P+DMSO).After 4 weeks,maxillary molar segments were assessed via micro-computed tomography(CT)and hematoxylin and eosin(HE)staining.Serum tumor necrosis factor-α(TNF-α)levels were measured by enzyme-linked immunosorbent assay(ELISA).Results Higher expression of the Jmjd3 gene and JMJD3 protein was detected in human inflamed gingiva than in healthy gingiva(P<0.05).GSK-J4 administration reversed alveolar bone absorption[i.e.,reduced alveolar bone crest(ABC)-cementoenamel junction(CEJ)distance],reduced inflammatory cell accumulation at the crest of the alveolar bone,and alleviated serum TNF-αlevels in rats with periodontitis.Moreover,the number of H3K27me3-positive nuclei was greater in model rats treated with GSK J4 than in model rats.Conclusions The histone demethylase inhibitor GSK-J4 attenuated periodontal bone loss and inflammation in a rat periodontitis model by targeting JMJD3.展开更多
The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV c...The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.展开更多
Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytoki...Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.展开更多
Epidemiological studies indicate a strong correlation between various types of human cancer and dietary factors,whereas the specific mechanisms remain to be fully elucidated.Epigenetic alterations,such as DNA methylat...Epidemiological studies indicate a strong correlation between various types of human cancer and dietary factors,whereas the specific mechanisms remain to be fully elucidated.Epigenetic alterations,such as DNA methylation,histone modifications,and noncoding RNA,are influenced by dietary components,especially phytochemicals and nutrients that participate in one-carbon metabolism.These alterations significantly impact cancer occurrence and progression.Consequently,epigenetic pathways may mediate the effects of diet on cancer risk.This review synthesizes the current information regarding the association of epigenetic alterations with cancer initiation and development,as well as the mechanisms by which diet exerts its influence on these changes.The goal of this minireview is to enhance the understanding of the roles of diet on epigenetic alterations to improve cancer prevention and treatment through diet.展开更多
Aegilops speltoides,the closest ancestor of the wheat B subgenome,has been well studied genomically.However,the epigenetic landscape of Ae.speltoides and the effects of epigenetics on its growth and development remain...Aegilops speltoides,the closest ancestor of the wheat B subgenome,has been well studied genomically.However,the epigenetic landscape of Ae.speltoides and the effects of epigenetics on its growth and development remain poorly understood.Here,we present a comprehensive multi-omics atlas of leaves and roots in Ae.speltoides,encompassing transcriptome,DNA methylation,histone modifications,and small RNA profiling.Divergent DNA methylation levels were detected between leaves and roots,and were associated with differences in accumulated 24-nt siRNAs.DNA methylation changes in promoters and gene bodies showed strong connections with altered expression between leaves and roots.Transcriptional regulatory networks(TRN)reconstructed between leaves and roots were driven by tissue-specific TF families.DNA methylation and histone modification act together as switches that shape root and leaf morphogenesis by modulating the binding of tissue-specific TFs to their target genes.The TRNs in leaves and roots reshaped during wheat polyploidization were associated with alterations in epigenetic modi-fications.Collectively,these results not only shed light on the critical contribution of epigenetic regulation in the morphogenesis of leaves and roots in Ae.speltoides but also provide new insights for future investigations into the complex interplay of genetic and epigenetic factors in the developmental biology of common wheat.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.
基金supported by the Natural Science Foundation of Guangdong Province(No.2024A1515010605,2022A1515140034)Discipline Construction Project of Guangdong Medical University(No.4SG24007G,4SG22302P)+1 种基金Medical Scientific Research Fund of Guangdong Province(No.B2024193)Dongguan Social Development and Scientific Technology Project,China(No.20231800936562).
文摘Lactylation is one of the post-translational modifications of proteins,a process in which lactyl residues bind to the lysine residues of proteins.This modification can alter the structure,stability,and function of proteins,which in turn regulates cellular metabolism,aging,and the onset of disease.This review classifies proteins with lactylation effects into histones and non-histone proteins and analyzes their functional roles when lactylation occurs.The in-depth exploration of lactylation is still in its infancy,and many aspects of its regulation,functional significance and therapeutic potential need to be further explored.
基金supported by the Tianjin Stomatological Hospital MD and PhD Key Program(No.2019BSZD11)Periodontal Key Discipline Project of Tianjin Stomatological Hospital(2022P02)+1 种基金the Science and Technology Project of Tianjin Health Commission(No.ZC20039)the High-level Talents in the Medical/Health Care Industry-Young Medical Elites(No.TJSQNYXXR-D2-114).
文摘Objective To investigate the treatment effect of the histone demethylase inhibitor GSK-J4,a small molecule that inhibits the demethylase activity of Jumonji domain-containing protein 3(JMJD3),in the treatment of periodontitis.Methods Gingival tissues from patients with moderate to severe chronic periodontitis and healthy controls were collected to evaluate JMJD3 expression via real-time quantitative reverse transcription PCR(RT-qPCR)and immunohistochemistry(IHC).Next,Sprague–Dawley(SD)rats were used to investigate the effect of GSK-J4 in vivo.The experimental periodontitis model was induced by upper first molar ligation and gingival sulcus injection of Porphyromonas gingivalis.The rats were divided into a healthy group,a periodontitis group,periodontitis plus GSK-J4 treatment groups(P+GSK-J415 mg/kg or 25 mg/kg),and a periodontitis plus dimethyl sulfoxide(DMSO)group(P+DMSO).After 4 weeks,maxillary molar segments were assessed via micro-computed tomography(CT)and hematoxylin and eosin(HE)staining.Serum tumor necrosis factor-α(TNF-α)levels were measured by enzyme-linked immunosorbent assay(ELISA).Results Higher expression of the Jmjd3 gene and JMJD3 protein was detected in human inflamed gingiva than in healthy gingiva(P<0.05).GSK-J4 administration reversed alveolar bone absorption[i.e.,reduced alveolar bone crest(ABC)-cementoenamel junction(CEJ)distance],reduced inflammatory cell accumulation at the crest of the alveolar bone,and alleviated serum TNF-αlevels in rats with periodontitis.Moreover,the number of H3K27me3-positive nuclei was greater in model rats treated with GSK J4 than in model rats.Conclusions The histone demethylase inhibitor GSK-J4 attenuated periodontal bone loss and inflammation in a rat periodontitis model by targeting JMJD3.
基金supported by the National Key R&D Program of China(No.2022YFA1303600 and No.2023YFC2306800)the National Natural Science Foundation of China(No.82372235 and No.82272315)the Sanming Project of Medicine in Shenzhen(No.SZSM202311032).
文摘The persistence of covalently closed circular DNA(cccDNA)in hepatitis B virus(HBV)-infected hepatocytes remains a major obstacle to effective antiviral treatment.Understanding the molecular mechanisms regulating HBV cccDNA transcription is essential for developing novel therapeutic strategies.In this study,we investigated the role of RNA binding motif protein 25(RBM25)in HBV replication,focusing on its interaction with cccDNA and its regulation of host transcription factors.The results demonstrated that RBM25 knockdown markedly inhibited HBV replication,reducing levels of HBV DNA,hepatitis B e antigen(HBeAg),hepatitis B surface antigen(HBsAg),HBV RNA,and L-HBs in HBV-replicating and infected cell models.Consistent results were observed in a mouse model hydrodynamically injected with 1.2HBV plasmid.Conversely,RBM25 overexpression significantly enhanced HBV replication.Mechanistically,RBM25 promoted HBV promoter activities by binding to cccDNA through its RE/RD and PWI domains.This effect was mediated by increased Yin Yang 1(YY1)expression,which enhanced acetylation of cccDNA-bound histones,promoting HBV transcription.Furthermore,RBM25 expression was upregulated and translocated to the nucleus following core protein expression and accumulation,while overexpression of RBM25 promoted core protein degradation.In conclusion,this study demonstrates that RBM25 is a novel host factor that enhances HBV replication by upregulating YY1-dependent transcriptional activation of cccDNA.It also reveales a reciprocal regulatory mechanism between the HBV core protein and RBM25,which helps sustain HBV replication.
基金supported by the National Natural Science Foundation of China,Nos.32070735(to QL),82371321(to QL),82171270(to ZL)Public Service Platform for Artificial Intelligence Screening and Auxiliary Diagnosis for the Medical and Health Industry,Ministry of Industry and Information Technology of the People's Republic of China,No.2020-0103-3-1(to ZL)+2 种基金the Natural Science Foundation of Beijing,No.Z200016(to ZL)Beijing Talents Project,No.2018000021223ZK03(to ZL)Beijing Municipal Committee of Science and Technology,No.Z201100005620010(to ZL)。
文摘Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.
文摘Epidemiological studies indicate a strong correlation between various types of human cancer and dietary factors,whereas the specific mechanisms remain to be fully elucidated.Epigenetic alterations,such as DNA methylation,histone modifications,and noncoding RNA,are influenced by dietary components,especially phytochemicals and nutrients that participate in one-carbon metabolism.These alterations significantly impact cancer occurrence and progression.Consequently,epigenetic pathways may mediate the effects of diet on cancer risk.This review synthesizes the current information regarding the association of epigenetic alterations with cancer initiation and development,as well as the mechanisms by which diet exerts its influence on these changes.The goal of this minireview is to enhance the understanding of the roles of diet on epigenetic alterations to improve cancer prevention and treatment through diet.
基金supported by the National Key Research and Development Program of China(2023YFD1200403).
文摘Aegilops speltoides,the closest ancestor of the wheat B subgenome,has been well studied genomically.However,the epigenetic landscape of Ae.speltoides and the effects of epigenetics on its growth and development remain poorly understood.Here,we present a comprehensive multi-omics atlas of leaves and roots in Ae.speltoides,encompassing transcriptome,DNA methylation,histone modifications,and small RNA profiling.Divergent DNA methylation levels were detected between leaves and roots,and were associated with differences in accumulated 24-nt siRNAs.DNA methylation changes in promoters and gene bodies showed strong connections with altered expression between leaves and roots.Transcriptional regulatory networks(TRN)reconstructed between leaves and roots were driven by tissue-specific TF families.DNA methylation and histone modification act together as switches that shape root and leaf morphogenesis by modulating the binding of tissue-specific TFs to their target genes.The TRNs in leaves and roots reshaped during wheat polyploidization were associated with alterations in epigenetic modi-fications.Collectively,these results not only shed light on the critical contribution of epigenetic regulation in the morphogenesis of leaves and roots in Ae.speltoides but also provide new insights for future investigations into the complex interplay of genetic and epigenetic factors in the developmental biology of common wheat.
