Gene expression is regulated by chromatin architecture and epigenetic remodeling in cell homeostasis and pathologies.Histone modifications act as the key factors to modulate the chromatin accessibility.Different histo...Gene expression is regulated by chromatin architecture and epigenetic remodeling in cell homeostasis and pathologies.Histone modifications act as the key factors to modulate the chromatin accessibility.Different histone modifications are strongly associated with the localization of chromatin.Heterochromatin primarily localizes at the nuclear periphery,where it interacts with lamina proteins to suppress gene expression.In this review,we summarize the potential bridges that have regulatory functions of histone modifications in chromatin organization and transcriptional regulation at the nuclear periphery.We use lamina-associated domains(LADs)as examples to elucidate the biological roles of the interactions between histone modifications and nuclear lamina in cell differentiation and development.In the end,we highlight the technologies that are currently used to identify and visualize histone modifications and LADs,which could provide spatiotemporal information for understanding their regulatory functions in gene expression and discovering new targets for diseases.展开更多
Epigenetics is the discipline of regulating cellular activity through chemical modification or modulation of noncoding RNAs without altering the nucleotide sequence.Studies on this topic include the exploration of DNA...Epigenetics is the discipline of regulating cellular activity through chemical modification or modulation of noncoding RNAs without altering the nucleotide sequence.Studies on this topic include the exploration of DNA methylation,histone modification,noncoding RNA regulation,and chromatin remodeling.Derived from the apical tissues of young permanent teeth,stem cells from apical papilla are odontogenic adult stem cells with high proliferation,self-renewal capacity,and differentiation potential.These cells play crucial roles in root formation and development.This article focuses on the two epigenetic regulatory mechanisms of histone modifications and non-coding RNA.This review summarizes,generalizes,and evaluates the status of research on the epigenetic regulation of the multidirectional differentiation of stem cells from the apical papilla,aiming to explore the mechanisms underlying the multidirectional differentiation process of these stem cells.展开更多
The basic unit of chromatin is the nucleosomal core particle, containing 147 bp of DNA that wraps twice around an octamer of core histones. The core histones bear a highly dynamic N-terminal amino acid tail around 20-...The basic unit of chromatin is the nucleosomal core particle, containing 147 bp of DNA that wraps twice around an octamer of core histones. The core histones bear a highly dynamic N-terminal amino acid tail around 20-35 residues in length and rich in basic amino acids. These tails extending from the surface of nucleosome play an important role in folding of nucleosomal arrays into higher order chromatin structure, which plays an important role in eukaryotic gene regulation. The amino terminal tails protruding from the nuclesomes get modified by the addition of small groups such as methyl, acetyl and phosphoryl groups. In this review, we focus on these complex modi- fication patterns and their biological functions. Moreover, these modifications seem to be part of a complex scheme where distinct histone modifications act in a sequential manner or in combination to form a ＂histone code＂ read by other proteins to control the structure and/or function of the chromatin fiber. Errors in this histone code may be involved in many human diseases especially cancer, the nature of which could be therapeutically exploited. Increasing evidence suggests that many proteins bear multiple, distinct modifications, and the ability of one modification to antagonize or synergize the deposition of another can have significant biological consequences.展开更多
Plants grow in dynamic environments where they receive diverse environmental signals.Swift and precise control of gene expression is essential for plants to align their development and metabolism with fluctuating surr...Plants grow in dynamic environments where they receive diverse environmental signals.Swift and precise control of gene expression is essential for plants to align their development and metabolism with fluctuating surroundings.Modifications on histones serve as histone code" to specify chromatin and gene activities.Different modifications execute distinct functions on the chromatin,promoting either active transcription or gene silencing.Histone writers,erasers,and readers mediate the regulation of histone modifications by catalyzing,removing,and recognizing modifications,respectively.Growing evidence indicates the important function of histone modifications in plant development and environmental responses.Histone modifications also serve as environmental memory for plants to adapt to environmental changes.Here we review recent progress on the regulation of histone modifications in plants,the impact of histone modifications on environment-controlled developmental transitions including germination and flowering,and the role of histone modifications in environmental memory.展开更多
Histone methylation is one of the most widely studied post-transcriptional modifications. It is thought to be an important epigenetic event that is closely associated with cell fate determination and differentiation. ...Histone methylation is one of the most widely studied post-transcriptional modifications. It is thought to be an important epigenetic event that is closely associated with cell fate determination and differentiation. To explore the spatiotemporal expression of histone H3 lysine 4trimethylation（H3K4me3） and histone H3 lysine 27 trimethylation（H3K27me3） epigenetic marks and methylation or demethylation transferases in tooth organ development, we measured the expression of SET7, EZH2, KDM5 B and JMJD3 via immunohistochemistry and quantitative polymerase chain reaction（qP CR） analysis in the first molar of BALB/c mice embryos at E13.5, E15.5, E17.5, P0 and P3, respectively. We also measured the expression of H3K4me3 and H3K27me3 with immunofluorescence staining. During murine tooth germ development, methylation or demethylation transferases were expressed in a spatial–temporal manner. The bivalent modification characterized by H3K4me3 and H3K27me3 can be found during the tooth germ development, as shown by immunofluorescence. The expression of SET7, EZH2 as methylation transferases and KDM5 B and JMJD3 as demethylation transferases indicated accordingly with the expression of H3K4me3 and H3K27me3 respectively to some extent. The bivalent histone may play a critical role in tooth organ development via the regulation of cell differentiation.展开更多
In addition to DNA sequence information, site-specific histone modifications are another important determinant of gene expression in a eukaryotic organism. We selected four modification sites in common histones that a...In addition to DNA sequence information, site-specific histone modifications are another important determinant of gene expression in a eukaryotic organism. We selected four modification sites in common histones that are known to significantly impact chromatin function and generated monoclonal or polyclonal antibodies that recognize each of those site-specific modifications. We used these antibodies to demonstrate that the site-specific histone modification levels remain relatively constant in different organs of the same organism. We also compared the levels of selected histone modifications among several representative organisms and found that site-specific modifications are highly variable among different organisms, providing new insight into the evolutionary divergence of specific histone modifications.展开更多
Histone modifications are key factors in chromatin packaging,and are responsible for gene regulation during cell fate determination and development.Abnormal alterations in histone modifications potentially affect the ...Histone modifications are key factors in chromatin packaging,and are responsible for gene regulation during cell fate determination and development.Abnormal alterations in histone modifications potentially affect the stability of the genome and disrupt gene expression patterns,leading to many diseases,including cancer.In recent years,mounting evidence has shown that various histone modifications altered by aberrantly expressed modifier enzymes contribute to tumor development and metastasis through the induction of epigenetic,transcriptional,and phenotypic changes.In this review,we will discuss the existing histone modifications,both well-studied and rare ones,and their roles in solid tumors and hematopoietic cancers,to identify the molecular pathways involved and investigate targeted therapeutic drugs to reorganize the chromatin and enhance cancer treatment efficiency.Finally,clinical inhibitors of histone modifications are summarized to better understand the developmental stage of cancer therapy in using these drugs to inhibit the histone modification enzymes.展开更多
Given that lactoferrin(LF)exerts an excellent protection of intestinal homeostasis,the underlying mechanisms,especially epigenetic regulations,are still unknown.This study aimed to investigate the effects of dietary L...Given that lactoferrin(LF)exerts an excellent protection of intestinal homeostasis,the underlying mechanisms,especially epigenetic regulations,are still unknown.This study aimed to investigate the effects of dietary LF epigenetically modulates the oxidative genes by histone modifications to ameliorate ileum inflammation of mice exposed to DON contaminated diet.As expected,we found in the morphology analysis that DON exposure increased ileum crypt depth(CD)and villus width(VW)but reduced villus height(VH)and VH:CD ratio compared to those of the vehicle group.Consistently,the elevated ROS and MDA,along with the decreased ATP,SOD,CAT,GSH,and complex I,III,V were observed in the DON-exposed mice ileum.In contrast,LF markedly ameliorated the impairments of morphological and biochemical indexes.Next,we conducted transcriptome analysis to explore the changed signaling pathways using the ileum RNA of the mice treated with DON or LF.Firstly,the cell cycle pathway genes were significantly downregulated in the DON-exposed mice,and LF improved the cell cycle profile.Again,gene ontology analysis showed that inflammation and oxidative stress were significantly activated by DON exposure,and these were recovered when the DON-exposed mice were supplemented with an LF diet.Consistent with these findings,the signaling pathways of the reduced oxidative phosphorylation and elevated TNFαwere also observed to be ameliorated by LF treatment.Importantly,histone modifications,including acetylation,methylation,and lactylation were suggested to be the vital players involved in the DON or LF treatment,in which LF significantly increased the loss of histone modifications on these genes.With a bioinformatics analysis and validation by qRT-PCR,the nuclear receptor NR5A2 was selected as a key master in the ileum of mice stimulated by DON.LF performed the benefit function on the NR5A2-mediated oxidative stress genes Ncoa4 and Prdx3 in the DON-exposed mice.Moreover,a ChIP-qPCR was used to verify that histone marks involving H3K9ac,H3K18ac,H3k27ac,H3K4me1,H3K9la,and H3K18la facilitated the epigenetic regulation of NR5A2-modulated actions.We conclude that dietary LF effectively ameliorated ileum lesions induced by DON in mice by modulating oxidative genes Ncoa4 and Prdx3 through histone modifications.展开更多
Nitrate availability in soil is highly variable and often a limiting factor for crop growth.Plants must acclimate rapidly to these fluctuations.The phytohormone cytokinin(CK)plays a pivotal role in nitrate signaling a...Nitrate availability in soil is highly variable and often a limiting factor for crop growth.Plants must acclimate rapidly to these fluctuations.The phytohormone cytokinin(CK)plays a pivotal role in nitrate signaling as a secondary growth regulator.However,the mechanisms that regulate CK action in response to fluctuating nitrate levels remain poorly understood.Here,we show that chromatin modification of IPT3,a key gene in CK biosynthesis,is crucial for growth acclimation to variable nitrate supply.Transcriptional regulation of IPT3 drives CK output in response to nitrate availability,thereby balancing root and shoot growth.This rapid and dynamic regulation is mediated by two antagonistic histone H3 modifications:trimethylation of lysine 27 of histone H3(H3K27me3)and H3K4me3.Using mutants defective in the deposition or removal of these modifications,we identify several chromatin effectors involved in these processes and confirm that nitrate-driven chromatin dynamics fine-tune CK biosynthesis.Our findings provide insights into the epigenetic regulatory mechanisms underlying CK biosynthesis and open new avenues faor enhancing plant acclimation to fluctuating nutrient environments.展开更多
DNA damage is a relatively common event in eukaryotic cell and may lead to genetic mutation and even cancer. DNA damage induces cellular responses that enable the cell either to repair the damaged DNA or cope with the...DNA damage is a relatively common event in eukaryotic cell and may lead to genetic mutation and even cancer. DNA damage induces cellular responses that enable the cell either to repair the damaged DNA or cope with the damage in an appropriate way. Histone proteins are also the fundamental building blocks of eukaryotic chromatin besides DNA, and many types of post-translational modifications often occur on tails of histones. Although the function of these modifications has remained elusive, there is ever-growing studies suggest that histone modifications play vital roles in several chromatin-based processes, such as DNA damage response. In this review, we will discuss the main histone modifications, and their functions in DNA damage response.展开更多
Mechanical stimulation is the key physical factor in cell environment.Mechanotransduction acts as a fundamental regulator of cell behavior,regulating cell proliferation,differentiation,apoptosis,and exhibiting specifi...Mechanical stimulation is the key physical factor in cell environment.Mechanotransduction acts as a fundamental regulator of cell behavior,regulating cell proliferation,differentiation,apoptosis,and exhibiting specific signature alterations during the pathological process.As research continues,the role of epigenetic science in mechanotransduction is attracting attention.However,the molecular mechanism of the synergistic effect between mechanotransduction and epigenetics in physiological and pathological processes has not been clarified.We focus on how histone modifications,as important components of epigenetics,are coordinated with multiple signaling pathways to control cell fate and disease progression.Specifically,we propose that histone modifications can form regulatory feedback loops with signaling pathways,that is,histone modifications can not only serve as downstream regulators of signaling pathways for target gene transcription but also provide feedback to regulate signaling pathways.Mechanotransduction and epigenetic changes could be potential markers and therapeutic targets in clinical practice.展开更多
Deposition of the histone variant H2A.Z at gene bodies regulates transcription by modifying chromatin accessibility in plants. However, the role of H2A.Z enrichment at the promoter and enhancer regions is unclear, and...Deposition of the histone variant H2A.Z at gene bodies regulates transcription by modifying chromatin accessibility in plants. However, the role of H2A.Z enrichment at the promoter and enhancer regions is unclear, and how H2A.Z interacts with other mechanisms of chromatin modification to regulate gene expression remains obscure. Here, we mapped genome-wide H2A.Z, H3K4me3, H3K27me3, Pol II, and nucleosome occupancy in Arabidopsis inflorescence. We showed that H2A.Z preferentially associated with H3K4me3 at promoters, while it was found with H3K27me3 at enhancers, and that H2A.Z deposition negatively correlated with gene expression. In addition, we demonstrated that H2A.Z represses gene expression by establishing low gene accessibility at ＋1 nucleosome and maintaining high gene accessibility at -1 nucleosome. We further showed that the high measures of gene responsiveness correlate with the H2A.Z-associated closed ＋1 nucleosome structure. Moreover, we found that H2A.Z represses enhancer activity by promoting H3K27me3 and preventing H3K4me3 histone modifications. This study provides a framework for future studies of H2A.Z functions and opens up new aspects for decoding the interplay between chromatin modification and histone variants in transcrip- tional control.展开更多
DNA methylation and histone modification are evolutionarily conserved epigenetic modifications that are crucial for the expression regulation of abiotic stress-responsive genes in plants.Dynamic changes in gene expres...DNA methylation and histone modification are evolutionarily conserved epigenetic modifications that are crucial for the expression regulation of abiotic stress-responsive genes in plants.Dynamic changes in gene expression levels can result from changes in DNA methylation and histone modifications.In the last two decades,how epigenetic machinery regulates abiotic stress responses in plants has been extensively studied.Here,based on recent publications,we review how DNA methylation and histone modifications impact gene expression regulation in response to abiotic stresses such as drought,abscisic acid,high salt,extreme temperature,nutrient deficiency or toxicity,and ultraviolet B exposure.We also review the roles of epigenetic mechanisms in the formation of transgenerational stress memory.We posit that a better understanding of the epigenetic underpinnings of abiotic stress responses in plants may facilitate the design of more stress-resistant or-resilient crops,which is essential for coping with global warming and extreme environments.展开更多
Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and developm...Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and development remain poorly understood.Our previous studies show that extracellular heat shock protein 70-like protein(HSP70L1)is a potent adjuvant of Th1 responses via stimulating DCs when released from cells;however,the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown.Herein,we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression,in contrast to the adjuvant activity of extracellular HSP70L1.The stability of intracellular HSP70L1 is dependent on DNAJC2,a known epigenetic regulator.Mechanistically,intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory,MHC and STAT3 genes.Thus,intracellular HSP70L1 is an inhibitor of human DC maturation.Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.展开更多
Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription.Post-translational modifications of the histones play a key role in epigene...Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription.Post-translational modifications of the histones play a key role in epigenetic regulation of gene transcription.In this review,we provide an overview of recent studies on the role of histone modifications in carcinogenesis.Since tumour-selective ligands such as tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)are well-considered as promising anti-tumour therapies,we summarise strategies for improving TRAIL sensitivity by inhibiting aberrant histone modifications in cancers.In this perspective we also discuss new epigenetic drug targets for enhancing TRAIL-mediated apoptosis.展开更多
Chronic kidney disease(CKD)has emerged as a formidable global health challenge,with a marked increase in its incidence,prevalence,and mortality rates.Renal fibrosis is a central pathophysiological process that drives ...Chronic kidney disease(CKD)has emerged as a formidable global health challenge,with a marked increase in its incidence,prevalence,and mortality rates.Renal fibrosis is a central pathophysiological process that drives the progression of CKD to end-stage renal disease.Despite its crucial role in CKD progression,effective clinical interventions to delay or mitigate renal fibrosis remain limited.A deeper understanding of the molecular mechanisms underlying renal fibrosis,along with the identification of potential drug targets and the development of novel therapeutics,holds immense research significance and clinical value for the prevention and treatment of CKD.In recent years,epigenetic research has garnered widespread attention and plays a pivotal role in various disease processes.Against this backdrop,the mechanisms by which epigenetic modifications exert their effects on renal fibrosis are gradually being elucidated,offering novel insights into the understanding of CKD.In this review,we summarize and analyze the intricate regulatory network of epigenetic modifications in renal fibrosis.We explore the promising antifibrotic effects demonstrated by various epigenetically modified drugs in fibrotic kidney models and discuss the challenges and opportunities in current research.These findings provide crucial insights for a deeper understanding of the molecular mechanisms underlying renal fibrosis and the development of novel therapeutic approaches.展开更多
BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and ...BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.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
Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more ...Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.展开更多
Pancreatic cancer(PC)is an aggressive human cancer.Appropriate methods for the diagnosis and treatment of PC have not been found at the genetic level,thus making epigenetics a promising research path in studies of PC....Pancreatic cancer(PC)is an aggressive human cancer.Appropriate methods for the diagnosis and treatment of PC have not been found at the genetic level,thus making epigenetics a promising research path in studies of PC.Histone methylation is one of the most complicated types of epigenetic modifications and has proved crucial in the development of PC.Histone methylation is a reversible process regulated by readers,writers,and erasers.Some writers and erasers can be recognized as potential biomarkers and candidate therapeutic targets in PC because of their unusual expression in PC cells compared with normal pancreatic cells.Based on the impact that writers have on the development of PC,some inhibitors of writers have been developed.However,few inhibitors of erasers have been developed and put to clinical use.Meanwhile,there is not enough research on the reader domains.Therefore,the study of erasers and readers is still a promising area.This review focuses on the regulatory mechanism of histone methylation,and the diagnosis and chemotherapy of PC based on it.The future of epigenetic modification in PC research is also discussed.展开更多
基金financially supported by the National Natural Science Foundation of China(32100450 and 32471370 to Q.P.,12372302 to J.Q.)the Guangdong Pearl River Talent Program(2021QN02Y781 to Q.P.)the Evident&Shenzhen Bay Laboratory Joint Optical Microscopic Imaging Technology Development Program(S234602004-1 to Q.P.).
文摘Gene expression is regulated by chromatin architecture and epigenetic remodeling in cell homeostasis and pathologies.Histone modifications act as the key factors to modulate the chromatin accessibility.Different histone modifications are strongly associated with the localization of chromatin.Heterochromatin primarily localizes at the nuclear periphery,where it interacts with lamina proteins to suppress gene expression.In this review,we summarize the potential bridges that have regulatory functions of histone modifications in chromatin organization and transcriptional regulation at the nuclear periphery.We use lamina-associated domains(LADs)as examples to elucidate the biological roles of the interactions between histone modifications and nuclear lamina in cell differentiation and development.In the end,we highlight the technologies that are currently used to identify and visualize histone modifications and LADs,which could provide spatiotemporal information for understanding their regulatory functions in gene expression and discovering new targets for diseases.
文摘Epigenetics is the discipline of regulating cellular activity through chemical modification or modulation of noncoding RNAs without altering the nucleotide sequence.Studies on this topic include the exploration of DNA methylation,histone modification,noncoding RNA regulation,and chromatin remodeling.Derived from the apical tissues of young permanent teeth,stem cells from apical papilla are odontogenic adult stem cells with high proliferation,self-renewal capacity,and differentiation potential.These cells play crucial roles in root formation and development.This article focuses on the two epigenetic regulatory mechanisms of histone modifications and non-coding RNA.This review summarizes,generalizes,and evaluates the status of research on the epigenetic regulation of the multidirectional differentiation of stem cells from the apical papilla,aiming to explore the mechanisms underlying the multidirectional differentiation process of these stem cells.
文摘The basic unit of chromatin is the nucleosomal core particle, containing 147 bp of DNA that wraps twice around an octamer of core histones. The core histones bear a highly dynamic N-terminal amino acid tail around 20-35 residues in length and rich in basic amino acids. These tails extending from the surface of nucleosome play an important role in folding of nucleosomal arrays into higher order chromatin structure, which plays an important role in eukaryotic gene regulation. The amino terminal tails protruding from the nuclesomes get modified by the addition of small groups such as methyl, acetyl and phosphoryl groups. In this review, we focus on these complex modi- fication patterns and their biological functions. Moreover, these modifications seem to be part of a complex scheme where distinct histone modifications act in a sequential manner or in combination to form a ＂histone code＂ read by other proteins to control the structure and/or function of the chromatin fiber. Errors in this histone code may be involved in many human diseases especially cancer, the nature of which could be therapeutically exploited. Increasing evidence suggests that many proteins bear multiple, distinct modifications, and the ability of one modification to antagonize or synergize the deposition of another can have significant biological consequences.
基金supported by the startup funding from State Key Laboratory of Plant Genomics and Institute of Genetics and Developmental Biology,Chinese Academy of Sciences
文摘Plants grow in dynamic environments where they receive diverse environmental signals.Swift and precise control of gene expression is essential for plants to align their development and metabolism with fluctuating surroundings.Modifications on histones serve as histone code" to specify chromatin and gene activities.Different modifications execute distinct functions on the chromatin,promoting either active transcription or gene silencing.Histone writers,erasers,and readers mediate the regulation of histone modifications by catalyzing,removing,and recognizing modifications,respectively.Growing evidence indicates the important function of histone modifications in plant development and environmental responses.Histone modifications also serve as environmental memory for plants to adapt to environmental changes.Here we review recent progress on the regulation of histone modifications in plants,the impact of histone modifications on environment-controlled developmental transitions including germination and flowering,and the role of histone modifications in environmental memory.
基金supported by National Science Foundation of China (Grant No. 81371136) to Xue-Dong ZhouNational Science Foundation of China (Grant No. 81200760 and 81470711) to Li-Wei Zheng
文摘Histone methylation is one of the most widely studied post-transcriptional modifications. It is thought to be an important epigenetic event that is closely associated with cell fate determination and differentiation. To explore the spatiotemporal expression of histone H3 lysine 4trimethylation（H3K4me3） and histone H3 lysine 27 trimethylation（H3K27me3） epigenetic marks and methylation or demethylation transferases in tooth organ development, we measured the expression of SET7, EZH2, KDM5 B and JMJD3 via immunohistochemistry and quantitative polymerase chain reaction（qP CR） analysis in the first molar of BALB/c mice embryos at E13.5, E15.5, E17.5, P0 and P3, respectively. We also measured the expression of H3K4me3 and H3K27me3 with immunofluorescence staining. During murine tooth germ development, methylation or demethylation transferases were expressed in a spatial–temporal manner. The bivalent modification characterized by H3K4me3 and H3K27me3 can be found during the tooth germ development, as shown by immunofluorescence. The expression of SET7, EZH2 as methylation transferases and KDM5 B and JMJD3 as demethylation transferases indicated accordingly with the expression of H3K4me3 and H3K27me3 respectively to some extent. The bivalent histone may play a critical role in tooth organ development via the regulation of cell differentiation.
文摘In addition to DNA sequence information, site-specific histone modifications are another important determinant of gene expression in a eukaryotic organism. We selected four modification sites in common histones that are known to significantly impact chromatin function and generated monoclonal or polyclonal antibodies that recognize each of those site-specific modifications. We used these antibodies to demonstrate that the site-specific histone modification levels remain relatively constant in different organs of the same organism. We also compared the levels of selected histone modifications among several representative organisms and found that site-specific modifications are highly variable among different organisms, providing new insight into the evolutionary divergence of specific histone modifications.
基金supported by grants from National Natural Science Foundation of China(grant number:42125707,41931291)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(grant number:2019PT310027)+1 种基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(grant number:2021-RC310-006,2021-I2M-1-018,2021-RC310-018,2020-RC310-008)China Postdoc-toral Science Foundation(grant number:2022M710454).
文摘Histone modifications are key factors in chromatin packaging,and are responsible for gene regulation during cell fate determination and development.Abnormal alterations in histone modifications potentially affect the stability of the genome and disrupt gene expression patterns,leading to many diseases,including cancer.In recent years,mounting evidence has shown that various histone modifications altered by aberrantly expressed modifier enzymes contribute to tumor development and metastasis through the induction of epigenetic,transcriptional,and phenotypic changes.In this review,we will discuss the existing histone modifications,both well-studied and rare ones,and their roles in solid tumors and hematopoietic cancers,to identify the molecular pathways involved and investigate targeted therapeutic drugs to reorganize the chromatin and enhance cancer treatment efficiency.Finally,clinical inhibitors of histone modifications are summarized to better understand the developmental stage of cancer therapy in using these drugs to inhibit the histone modification enzymes.
基金funded by Jiangsu Higher Education Key Natural Science Research Program(21 KJA230002)Yangzhou Hanjiang sci-tech project.Jiangsu Higher Education Key Natural Science Research Program,21 KJA230002,Dejun Ji,Yangzhou Hanjiang sci-tech project。
文摘Given that lactoferrin(LF)exerts an excellent protection of intestinal homeostasis,the underlying mechanisms,especially epigenetic regulations,are still unknown.This study aimed to investigate the effects of dietary LF epigenetically modulates the oxidative genes by histone modifications to ameliorate ileum inflammation of mice exposed to DON contaminated diet.As expected,we found in the morphology analysis that DON exposure increased ileum crypt depth(CD)and villus width(VW)but reduced villus height(VH)and VH:CD ratio compared to those of the vehicle group.Consistently,the elevated ROS and MDA,along with the decreased ATP,SOD,CAT,GSH,and complex I,III,V were observed in the DON-exposed mice ileum.In contrast,LF markedly ameliorated the impairments of morphological and biochemical indexes.Next,we conducted transcriptome analysis to explore the changed signaling pathways using the ileum RNA of the mice treated with DON or LF.Firstly,the cell cycle pathway genes were significantly downregulated in the DON-exposed mice,and LF improved the cell cycle profile.Again,gene ontology analysis showed that inflammation and oxidative stress were significantly activated by DON exposure,and these were recovered when the DON-exposed mice were supplemented with an LF diet.Consistent with these findings,the signaling pathways of the reduced oxidative phosphorylation and elevated TNFαwere also observed to be ameliorated by LF treatment.Importantly,histone modifications,including acetylation,methylation,and lactylation were suggested to be the vital players involved in the DON or LF treatment,in which LF significantly increased the loss of histone modifications on these genes.With a bioinformatics analysis and validation by qRT-PCR,the nuclear receptor NR5A2 was selected as a key master in the ileum of mice stimulated by DON.LF performed the benefit function on the NR5A2-mediated oxidative stress genes Ncoa4 and Prdx3 in the DON-exposed mice.Moreover,a ChIP-qPCR was used to verify that histone marks involving H3K9ac,H3K18ac,H3k27ac,H3K4me1,H3K9la,and H3K18la facilitated the epigenetic regulation of NR5A2-modulated actions.We conclude that dietary LF effectively ameliorated ileum lesions induced by DON in mice by modulating oxidative genes Ncoa4 and Prdx3 through histone modifications.
基金supported by the Programs for Promoting the Enhancement of Research Universities,Nagoya University(FY2019-2022)a KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas(no.JP17H06473S)from the Ministry of Education,Culture,Sports,Science and Technology+2 种基金JSPS KAKENHI Grants-in-Aid for Scientific Research(A)(nos.JP19H00931 and JP23H00324)a JSPS KAKENHI Grant-in-Aid for Early-Career Scientists(no.2824K18138)the Tokai Pathways to Global Excellence(T-GEx)program,part of the MEXT Strategic Professional Development Program for Young Researchers(no.0121an0002).
文摘Nitrate availability in soil is highly variable and often a limiting factor for crop growth.Plants must acclimate rapidly to these fluctuations.The phytohormone cytokinin(CK)plays a pivotal role in nitrate signaling as a secondary growth regulator.However,the mechanisms that regulate CK action in response to fluctuating nitrate levels remain poorly understood.Here,we show that chromatin modification of IPT3,a key gene in CK biosynthesis,is crucial for growth acclimation to variable nitrate supply.Transcriptional regulation of IPT3 drives CK output in response to nitrate availability,thereby balancing root and shoot growth.This rapid and dynamic regulation is mediated by two antagonistic histone H3 modifications:trimethylation of lysine 27 of histone H3(H3K27me3)and H3K4me3.Using mutants defective in the deposition or removal of these modifications,we identify several chromatin effectors involved in these processes and confirm that nitrate-driven chromatin dynamics fine-tune CK biosynthesis.Our findings provide insights into the epigenetic regulatory mechanisms underlying CK biosynthesis and open new avenues faor enhancing plant acclimation to fluctuating nutrient environments.
基金supported by the National Natural Science Foundation of China(8132100391319302+3 种基金31070691)Ministry of Science and Technology of China(2011CB504200)Ministry of Education of China(111 project)Peking University-Tsinghua University Center for Life Science
文摘DNA damage is a relatively common event in eukaryotic cell and may lead to genetic mutation and even cancer. DNA damage induces cellular responses that enable the cell either to repair the damaged DNA or cope with the damage in an appropriate way. Histone proteins are also the fundamental building blocks of eukaryotic chromatin besides DNA, and many types of post-translational modifications often occur on tails of histones. Although the function of these modifications has remained elusive, there is ever-growing studies suggest that histone modifications play vital roles in several chromatin-based processes, such as DNA damage response. In this review, we will discuss the main histone modifications, and their functions in DNA damage response.
基金the Department of Science and Technology of Jilin Province,China(No.20230101163JC and No.20210509003RQ)。
文摘Mechanical stimulation is the key physical factor in cell environment.Mechanotransduction acts as a fundamental regulator of cell behavior,regulating cell proliferation,differentiation,apoptosis,and exhibiting specific signature alterations during the pathological process.As research continues,the role of epigenetic science in mechanotransduction is attracting attention.However,the molecular mechanism of the synergistic effect between mechanotransduction and epigenetics in physiological and pathological processes has not been clarified.We focus on how histone modifications,as important components of epigenetics,are coordinated with multiple signaling pathways to control cell fate and disease progression.Specifically,we propose that histone modifications can form regulatory feedback loops with signaling pathways,that is,histone modifications can not only serve as downstream regulators of signaling pathways for target gene transcription but also provide feedback to regulate signaling pathways.Mechanotransduction and epigenetic changes could be potential markers and therapeutic targets in clinical practice.
文摘Deposition of the histone variant H2A.Z at gene bodies regulates transcription by modifying chromatin accessibility in plants. However, the role of H2A.Z enrichment at the promoter and enhancer regions is unclear, and how H2A.Z interacts with other mechanisms of chromatin modification to regulate gene expression remains obscure. Here, we mapped genome-wide H2A.Z, H3K4me3, H3K27me3, Pol II, and nucleosome occupancy in Arabidopsis inflorescence. We showed that H2A.Z preferentially associated with H3K4me3 at promoters, while it was found with H3K27me3 at enhancers, and that H2A.Z deposition negatively correlated with gene expression. In addition, we demonstrated that H2A.Z represses gene expression by establishing low gene accessibility at ＋1 nucleosome and maintaining high gene accessibility at -1 nucleosome. We further showed that the high measures of gene responsiveness correlate with the H2A.Z-associated closed ＋1 nucleosome structure. Moreover, we found that H2A.Z represses enhancer activity by promoting H3K27me3 and preventing H3K4me3 histone modifications. This study provides a framework for future studies of H2A.Z functions and opens up new aspects for decoding the interplay between chromatin modification and histone variants in transcrip- tional control.
基金the National Natural Science Foundation of China(31971822 and 32001448)Young Elite Scientists Sponsorship Program by Jilin Association for Science and Technology(QT2020011)the Fundamental Research Funds for the Central Universities(2412022QD028)。
文摘DNA methylation and histone modification are evolutionarily conserved epigenetic modifications that are crucial for the expression regulation of abiotic stress-responsive genes in plants.Dynamic changes in gene expression levels can result from changes in DNA methylation and histone modifications.In the last two decades,how epigenetic machinery regulates abiotic stress responses in plants has been extensively studied.Here,based on recent publications,we review how DNA methylation and histone modifications impact gene expression regulation in response to abiotic stresses such as drought,abscisic acid,high salt,extreme temperature,nutrient deficiency or toxicity,and ultraviolet B exposure.We also review the roles of epigenetic mechanisms in the formation of transgenerational stress memory.We posit that a better understanding of the epigenetic underpinnings of abiotic stress responses in plants may facilitate the design of more stress-resistant or-resilient crops,which is essential for coping with global warming and extreme environments.
基金We thank Yanfeng Li for the technical assistance.This work was supported by grants from the National Key R&D Program of China(2018YFA0507401)the National Natural Science Foundation of China(31670875 and 31470858).
文摘Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and development remain poorly understood.Our previous studies show that extracellular heat shock protein 70-like protein(HSP70L1)is a potent adjuvant of Th1 responses via stimulating DCs when released from cells;however,the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown.Herein,we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression,in contrast to the adjuvant activity of extracellular HSP70L1.The stability of intracellular HSP70L1 is dependent on DNAJC2,a known epigenetic regulator.Mechanistically,intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory,MHC and STAT3 genes.Thus,intracellular HSP70L1 is an inhibitor of human DC maturation.Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.
基金This research was partly funded by The Dutch Technology Foundation(STW)(No.11056)European Fund for Regional Development(KOP/EFRO)(No.068 and No.073).
文摘Epigenetic regulation refers to alterations to the chromatin template that collectively establish differential patterns of gene transcription.Post-translational modifications of the histones play a key role in epigenetic regulation of gene transcription.In this review,we provide an overview of recent studies on the role of histone modifications in carcinogenesis.Since tumour-selective ligands such as tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)are well-considered as promising anti-tumour therapies,we summarise strategies for improving TRAIL sensitivity by inhibiting aberrant histone modifications in cancers.In this perspective we also discuss new epigenetic drug targets for enhancing TRAIL-mediated apoptosis.
基金supported by the National Key R&D Program(2022YFC2502503,China)the National Natural Science Foundation of China(Nos.82270738 and 82400806)New Era Education Quality Improvement Project of Anhui Province(2024xscx053,China).
文摘Chronic kidney disease(CKD)has emerged as a formidable global health challenge,with a marked increase in its incidence,prevalence,and mortality rates.Renal fibrosis is a central pathophysiological process that drives the progression of CKD to end-stage renal disease.Despite its crucial role in CKD progression,effective clinical interventions to delay or mitigate renal fibrosis remain limited.A deeper understanding of the molecular mechanisms underlying renal fibrosis,along with the identification of potential drug targets and the development of novel therapeutics,holds immense research significance and clinical value for the prevention and treatment of CKD.In recent years,epigenetic research has garnered widespread attention and plays a pivotal role in various disease processes.Against this backdrop,the mechanisms by which epigenetic modifications exert their effects on renal fibrosis are gradually being elucidated,offering novel insights into the understanding of CKD.In this review,we summarize and analyze the intricate regulatory network of epigenetic modifications in renal fibrosis.We explore the promising antifibrotic effects demonstrated by various epigenetically modified drugs in fibrotic kidney models and discuss the challenges and opportunities in current research.These findings provide crucial insights for a deeper understanding of the molecular mechanisms underlying renal fibrosis and the development of novel therapeutic approaches.
文摘BACKGROUND Anterior cruciate ligament reconstruction(ACLR)is the dominant clinical modality for the treatment of anterior cruciate ligament injuries.The success of ACLR is largely dependent on tendon-bone healing,and stem cell biotherapies are often used to facilitate this process.Histone lactylation modifications are involved in the regulation of various diseases.Lactate dehydrogenase A(LDHA)has been shown to play an important role in exosomes.AIM To explore the regulation of tendon-bone healing after ACLR by LDHA in exosomes derived from bone marrow mesenchymal stem cells(BMSC-Exos).METHODS BMSC-Exos and LDHA were characterized and analyzed by transmission electron microscopy,qNano,immunofluorescence and western blotting assay.The corresponding low expression cell lines were obtained using RNA interference transfection;LDHA expression in rat bone tissues after ACLR was analyzed by western blotting.The volume of newborn bone tissues was monitored by micro-computed tomography imaging.Tendon and fibrocartilage regeneration were further analyzed and calculated by histological analysis,including hematoxylin and eosin and Safranin O-Fast green staining,respectively;LDHA levels of chondrocyte stem cells(CSPCs)after co-incubation with BMSC-Exos were analyzed by western blotting.Extracellularly secreted lactic acid content was determined by lactate assay kit.Cell viability was assessed by cell counting kit 8 assay,and the proliferation and differentiation ability of cells was further examined by the expression of collagen II,SOX9 and aggrecan.Histone H3K18 lactylation modification was analyzed by western blotting.H3K18 La binding on bone morphogenetic protein 7(BMP7)promoter was analyzed by chromatin immunoprecipitation-quantitative polymerase chain reaction;BMP7 promoter activity was analyzed by dual luciferase reporter gene;BMP7 protein expression was analyzed using quantitative polymerase chain reaction and western blotting.Then,the proliferation of CSPCs promoted by BMSC-Exos LDHA was analyzed by protein expression levels of LDHA,BMP7,collagen II,SOX9,aggrecan,extracellular lactate content,and cell counting kit 8 assay.RESULTS The spherical nanosized BMSC-Exos could be uptaken by CSPCs.LDHA was highly expressed in BMSC-Exos,which could infiltrate into the bone tissue of ACLR rats and promoted the generation of new bone tissue,as well as significantly increased the regeneration of tendon and fibrocartilage.Co-incubation of CSPCs with high-expressing LDHA BMSC-Exos increased the secretion of lactate content from CSPCs,cell viability,and the expression of markers related to cell proliferation and differentiation,including collagen II,SOX9,and aggrecan;LDHA in BMSC-Exos upregulated BMP7 through histone H3K18 lactate modification;high LDHA expression reversed the knockdown of BMP7,further increasing the proliferation and differentiation of CSPCs,thereby inducing cartilage formation.CONCLUSION LDHA in BMSC-Exos promotes BMP7 expression via H3K18 lactylation modification,which further promotes tendon-bone healing after ACLR.
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 Natural Science Foundation of China,No.82171062(to JFZ)Aier Eye Hospital Group Scientific Research Fund,No.AF2101D8(to LMG).
文摘Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.
文摘Pancreatic cancer(PC)is an aggressive human cancer.Appropriate methods for the diagnosis and treatment of PC have not been found at the genetic level,thus making epigenetics a promising research path in studies of PC.Histone methylation is one of the most complicated types of epigenetic modifications and has proved crucial in the development of PC.Histone methylation is a reversible process regulated by readers,writers,and erasers.Some writers and erasers can be recognized as potential biomarkers and candidate therapeutic targets in PC because of their unusual expression in PC cells compared with normal pancreatic cells.Based on the impact that writers have on the development of PC,some inhibitors of writers have been developed.However,few inhibitors of erasers have been developed and put to clinical use.Meanwhile,there is not enough research on the reader domains.Therefore,the study of erasers and readers is still a promising area.This review focuses on the regulatory mechanism of histone methylation,and the diagnosis and chemotherapy of PC based on it.The future of epigenetic modification in PC research is also discussed.
