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
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
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
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
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
Histone mimicry(HM)refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins.These motifs have the potential to interfere with host cell epigenome and counter...Histone mimicry(HM)refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins.These motifs have the potential to interfere with host cell epigenome and counteract antiviral response.Recent research shows that HM is critical for the pathogenesis and transmissibility of influenza virus and coronavirus.However,the distribution,characteristics,and functions of HM in eukaryotic viruses remain obscure.Herein,we developed a bioinformatic pipeline,Histone Motif Scan(HiScan),to identify HM motifs in viral proteins and predict their functions in silico.By analyzing 592,643 viral proteins using HiScan,we found that putative HM motifs were widely distributed in most viral proteins.Among animal viruses,the ratio of HM motifs between DNA viruses and RNA viruses was approximately 1.9:1,and viruses with smaller genomes had a higher density of HM motifs.Notably,coronaviruses exhibited an uneven distribution of HM motifs,with betacoronaviruses(including most human pathogenic coronaviruses)harboring more HM motifs than other coronaviruses,primarily in the NSP3,S,and N proteins.In summary,our virome-wide screening of HM motifs using HiScan revealed extensive but uneven distribution of HM motifs in most viral proteins,with a preference in DNA viruses.Viral HM may play an important role in modulating viral pathogenicity and virus-host interactions,making it an attractive area of research in virology and antiviral medication.展开更多
Nonobstructive azoospermia(NOA)is a severe and heterogeneous form of male factor infertility caused by dysfunction of spermatogenesis.Although various factors are well defined in the disruption of spermatogenesis,not ...Nonobstructive azoospermia(NOA)is a severe and heterogeneous form of male factor infertility caused by dysfunction of spermatogenesis.Although various factors are well defined in the disruption of spermatogenesis,not all aspects due to the heterogeneity of the disorder have been determined yet.In this review,we focus on the recent findings and summarize the current data on epigenetic mechanisms such as DNA methylation and different metabolites produced during methylation and demethylation and various types of small noncoding RNAs involved in the pathogenesis of different groups of NOA.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
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
Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulat...Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulating various amyloid-βoligomers in the brain,influenced by complex genetic and environmental factors.The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer’s disease are believed to primarily result from synaptic dysfunction.Throughout life,environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders.These changes,known as epigenetic modifications,also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity.In this context,we highlight recent advances in understanding the roles played by key components of the epigenetic machinery,specifically DNA methylation,histone modification,and microRNAs,in the development of Alzheimer’s disease,synaptic function,and activity-dependent synaptic plasticity.Moreover,we explore various strategies,including enriched environments,exposure to non-invasive brain stimulation,and the use of pharmacological agents,aimed at improving synaptic function and enhancing long-term potentiation,a process integral to epigenetic mechanisms.Lastly,we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer’s disease.We suggest that addressing Alzheimer’s disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.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
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.
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(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.
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funded by the National Natural Science Foundation of China(No.U2002218,32270170 and 81902070)the Fund of Hunan University(521119400156)the Science and Technology Innovation Program of Hunan Province(2024RC1028).
文摘Histone mimicry(HM)refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins.These motifs have the potential to interfere with host cell epigenome and counteract antiviral response.Recent research shows that HM is critical for the pathogenesis and transmissibility of influenza virus and coronavirus.However,the distribution,characteristics,and functions of HM in eukaryotic viruses remain obscure.Herein,we developed a bioinformatic pipeline,Histone Motif Scan(HiScan),to identify HM motifs in viral proteins and predict their functions in silico.By analyzing 592,643 viral proteins using HiScan,we found that putative HM motifs were widely distributed in most viral proteins.Among animal viruses,the ratio of HM motifs between DNA viruses and RNA viruses was approximately 1.9:1,and viruses with smaller genomes had a higher density of HM motifs.Notably,coronaviruses exhibited an uneven distribution of HM motifs,with betacoronaviruses(including most human pathogenic coronaviruses)harboring more HM motifs than other coronaviruses,primarily in the NSP3,S,and N proteins.In summary,our virome-wide screening of HM motifs using HiScan revealed extensive but uneven distribution of HM motifs in most viral proteins,with a preference in DNA viruses.Viral HM may play an important role in modulating viral pathogenicity and virus-host interactions,making it an attractive area of research in virology and antiviral medication.
文摘Nonobstructive azoospermia(NOA)is a severe and heterogeneous form of male factor infertility caused by dysfunction of spermatogenesis.Although various factors are well defined in the disruption of spermatogenesis,not all aspects due to the heterogeneity of the disorder have been determined yet.In this review,we focus on the recent findings and summarize the current data on epigenetic mechanisms such as DNA methylation and different metabolites produced during methylation and demethylation and various types of small noncoding RNAs involved in the pathogenesis of different groups of NOA.
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.
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.
基金supported by a grant from the Massachusetts Alzheimer’s Disease Research Center(5P50 AG 005134)(to SL).
文摘Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulating various amyloid-βoligomers in the brain,influenced by complex genetic and environmental factors.The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer’s disease are believed to primarily result from synaptic dysfunction.Throughout life,environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders.These changes,known as epigenetic modifications,also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity.In this context,we highlight recent advances in understanding the roles played by key components of the epigenetic machinery,specifically DNA methylation,histone modification,and microRNAs,in the development of Alzheimer’s disease,synaptic function,and activity-dependent synaptic plasticity.Moreover,we explore various strategies,including enriched environments,exposure to non-invasive brain stimulation,and the use of pharmacological agents,aimed at improving synaptic function and enhancing long-term potentiation,a process integral to epigenetic mechanisms.Lastly,we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer’s disease.We suggest that addressing Alzheimer’s disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.
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.
