Hearing loss,which currently affects more than 430 million individuals globally and is projected to exceed 700 million by 2050,predominantly manifests as sensorineural hearing loss(SNHL),for which existing technologie...Hearing loss,which currently affects more than 430 million individuals globally and is projected to exceed 700 million by 2050,predominantly manifests as sensorineural hearing loss(SNHL),for which existing technologies such as hearing aids and cochlear implants fail to restore natural auditory function.Research focusing on protecting inner ear hair cells(HCs)from harmful factors through the regulation of epigenetic modifications has gained significant attention in otology for its role in regulating gene expression without altering the DNA sequence,suggesting potential strategies for preventing and treating SNHL.By synthesizing relevant studies on the inner ear,this review summarizes the emerging roles of histone modifications,DNA methylation,and noncoding RNAs in HC damage,with a focus on their therapeutic potential through epigenetic modulation.Moreover,this review examines the therapeutic potential of epigenetic regulation for the prevention and treatment of SNHL,emphasizing the application of small-molecule epigenetic compounds and their efficacy in modulating gene expression to preserve and restore auditory function.展开更多
BACKGROUND Pancreatic cancer(PC)is one of the deadliest malignancies with an alarming mortality rate.Despite significant advancement in diagnostics and therapeutics,early diagnosis remains elusive causing poor prognos...BACKGROUND Pancreatic cancer(PC)is one of the deadliest malignancies with an alarming mortality rate.Despite significant advancement in diagnostics and therapeutics,early diagnosis remains elusive causing poor prognosis,marred by mutations and epigenetic modifications in key genes which contribute to disease progression.AIM To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley.METHODS A total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9(CA 19-9),tissue polypeptide specific antigen(TPS),carcinoembryonic antigen(CEA),vascular endothelial growth factor-A(VEGF-A),and epidermal growth factor receptor(EGFR).Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma(KRAS),Breast cancer type 2(BRCA-2),and deleted in pancreatic cancer-4(DPC-4)genes.However,epigenetic modifications(methylation of CpG islands)were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A(p16;CDKN2A),MutL homolog 1(hMLH1),and Ras association domain-containing protein 1(RASSF1A)genes.RESULTS We found significantly elevated levels of biological markers CA 19-9(P≤0.05),TPS(P≤0.05),CEA(P≤0.001),and VEGF(P≤0.001).Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12(16 subjects,P≤0.05),and 13(12 subjects,P≤0.05).However,we did not find a mutation in DPC-4(1203G>T)and BRCA-2(617delT)genes.Furthermore,epigenetic modification revealed that CpG methylation in 21(P≤0.05)and 4 subjects in the promoter regions of the p16 and hMLH1 gene,respectively.CONCLUSION In conclusion,CA 19-9,TPS,CEA,and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC.Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC.Additionally,methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.展开更多
Background:Retinal pigment epithelium(RPE)is vital for the homeostasis of the subretina including photoreceptors and choroid.Interestingly,our previous results suggested that the recently discovered lactate receptor G...Background:Retinal pigment epithelium(RPE)is vital for the homeostasis of the subretina including photoreceptors and choroid.Interestingly,our previous results suggested that the recently discovered lactate receptor GPR81 is abundantly expressed in RPE.To date,only one previous study has shown that activating GPR81 could enhance DNA repair by activating HDAC1.Consequently,we investigated whether GPR81 exhibits epigenetic modification in the subretina by using GPR81−/−mice.Methods:GPR81−/−mice and wide type littermates were generated on a background of C57BL/6J mice.The thicknesses of their choroid were evaluated by immunohistochemistry.Meanwhile,Q-PCR,western blot and choroid sprout assay were performed.In vitro,primary retinal pigment epithelium(pRPE)cells were isolated from mice,and cultured for treatments.Results:The thickness of choroid was reduced in GPR81−/−mice compared to GPR81+/+mice,suggesting that GPR81 is important for the integrity of choroid.In the choroid sprout assay,lactate treated RPE/choroid complex showed a significant increase in angiogenesis compared to controls while lactate treated KO RPE/choroid complex showed no difference compared to their controls.For Q-PCR,most of the genes screened elevated their expression in GPR81−/−mice compared to WT mice,suggesting epigenetic modification may exist,which were confirmed by histone acetylation and HDACs activity assay.Conclusions:Taking together,the lactate receptor GPR81 in RPE is very important for maintaining homeostasis of the subretina.This novel discovery sheds new light on the relationship between metabolism and epigenetic modification.展开更多
Epigenetic modifications modulate conformational structure of chromatin and consequently gene expression by enzyme-mediated chemical modifications of DNA and histones.The activities of epigenetic modifying enzymes dep...Epigenetic modifications modulate conformational structure of chromatin and consequently gene expression by enzyme-mediated chemical modifications of DNA and histones.The activities of epigenetic modifying enzymes depend on many co-substrates and cofactors,such as 2-oxoglutarate(2-OG),iron,S-adenosylmethionine(SAM),nicotinamide adenine dinucleotide(NAD+),flavin adenine dinucleotide(FAD),and acetyl-CoA.These factors are inter-connecting molecules that integrate cellular nutrient metabolism and redox homeostasis,two key regulators of cell proliferation,cell survival,and cell functions.Dysregulation of such delicate regulatory network has been implicated in many pathological conditions and also been increasingly recognized as an emerging mechanism responsible for environmental pollutant-induced adverse effects.In this review,we first summarize DNA and histone modifying enzymes and their essential factors,then discuss the metabolic sources and the redox regulatory roles of these enzymatic factors,and finally elaborate the mechanisms of how targeting such factors by environmental pollutants influences epigenetic regulation and perturbs cellular functions.展开更多
Dear Editor,Epigenetic modifications are regulatory codes that control gene expression and can be stably inherited without alterations in the genomic sequence(Allis and Jenuwein,2016).Numerous studies have demonstrate...Dear Editor,Epigenetic modifications are regulatory codes that control gene expression and can be stably inherited without alterations in the genomic sequence(Allis and Jenuwein,2016).Numerous studies have demonstrated that epigenetic modifications regulate critical biological processes in plants,such as growth,development,response to environmental stressors,and reproduction(Zhang et al.,2023;Bulgakov,2024).展开更多
Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention.Mitochondrial malate dehydrogenase(MDH2),an enzyme in the TCA cycle,was identi...Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention.Mitochondrial malate dehydrogenase(MDH2),an enzyme in the TCA cycle,was identified as an anti-aging target through activity-based protein profiling in present study.The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts.Glibenclamide(Gli),a classic anti-glycemic drug,was found to inhibit the activity of MDH2 and relieve fibroblast senescence in an MDH2-dependent manner.The anti-aging effects of Gli were also further validated in vivo,as it extended the lifespan and reduced the frailty index of naturally aged mice.Liver specific Mdh2 knockdown eliminated Gli’s beneficial effects in naturally aged mice,reducing p^(16INK4a) expression and hepatic fibrosis.Mechanistically,MDH2 inhibition or knockdown disrupted central carbon metabolism,then enhanced the methionine cycle flux,and subsequently promoted histone methylation.Notably,the tri-methylation of H3K27,identified as a crucial methylation site in reversing cellular senescence,was significantly elevated in hepatic tissues of naturally aged mice with Mdh2 knockdown.Taken together,these findings reveal that MDH2 inhibition or knockdown delays the aging process through metabolic-epigenetic regulation.Our research not only identified MDH2 as a potential therapeutic target and Gli as a lead compound for anti-aging drug development,but also shed light on the intricate interplay of metabolism and epigenetic modifications in aging.展开更多
Weight regain(WR)is a significant challenge in clinical treatment of obesity after successful weight loss.WR happens frequently after weight loss(WL)by dietary or life style adjustment although it also occurs in WL by...Weight regain(WR)is a significant challenge in clinical treatment of obesity after successful weight loss.WR happens frequently after weight loss(WL)by dietary or life style adjustment although it also occurs in WL by bariatric surgery and medications1-3.A general mechanism of WR is“obesity memory”,which refers to a stable gene expression pattern in adipose tissue from obesity.However,the molecular mechanisms underlying obesity memory remain unclear.Recently,Hinte et al.1 reported that obesity memory is mediated by an epigenetic mechanism in adipocytes of adipose tissue in a Nature article.展开更多
The mucosal barrier is crucial for intestinal homeostasis,and goblet cells are essential for maintaining the mucosal barrier integrity.The proviral integration site for Moloney murine leukemia virus-1(PIM1)kinase regu...The mucosal barrier is crucial for intestinal homeostasis,and goblet cells are essential for maintaining the mucosal barrier integrity.The proviral integration site for Moloney murine leukemia virus-1(PIM1)kinase regulates multiple cellular functions,but its role in intestinal homeostasis during colitis is unknown.Here,we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models,in the presence of intestinal microbiota.Epithelial PIM1 leads to decreased goblet cells,thus impairing resistance to colitis and colitis-associated colorectal cancer(CAC)in mice.Mechanistically,PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways.Interestingly,PIM1 interacts with histone deacetylase 2(HDAC2)and downregulates its level via phosphorylation,thereby altering the epigenetic profiles of Wnt signaling pathway genes.Collectively,these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis,which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.展开更多
The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiqui...The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.展开更多
DNA methylation is one of the main epigenetic phenomena affecting gene expression.It is an important mechanism for the development of embryo,growth and health of animals.As a key nutritional factor limiting the synthe...DNA methylation is one of the main epigenetic phenomena affecting gene expression.It is an important mechanism for the development of embryo,growth and health of animals.As a key nutritional factor limiting the synthesis of protein,methionine serves as the precursor of S-adenosylmethionine(SAM) in the hepatic one-carbon metabolism.The dietary fluctuation of methionine content can alter the levels of metabolic substrates in one-carbon metabolism,e.g.,the SAM,S-adenosylhomocysteine(SAH),and change the expression of genes related to the growth and health of animals by DNA methylation reactions.The ratio of SAM to SAH is called ‘methylation index' but it should be carefully explained because the complexity of methylation reaction.Alterations of methylation in a specific cytosine-guanine(Cp G)site,rather than the whole promoter region,might be enough to change gene expression.Aberrant methionine cycle may provoke molecular changes of one-carbon metabolism that results in deregulation of cellular hemostasis and health problems.The importance of DNA methylation has been underscored but the mechanisms of methionine affecting DNA methylation are poorly understood.Nutritional epigenomics provides a promising insight into the targeting epigenetic changes in animals from a nutritional standpoint,which will deepen and expand our understanding of genes,molecules,tissues,and animals in which methionine alteration influences DNA methylation and gene expression.展开更多
Fruit ripening is a complex developmental process made up of genetically programmed physiological and biochemical activities.It culminates in desirable changes in the structural and textural properties and is governed...Fruit ripening is a complex developmental process made up of genetically programmed physiological and biochemical activities.It culminates in desirable changes in the structural and textural properties and is governed by a complex regulatory network.Much is known about ethylene,one of the most important metabolites promoting the ripening of climacteric fruits.However,the dynamic interplay between phytohormones also plays an important part.Additional regulatory factors such as transcription factors(TFs)and epigenetic modifications also play vital role in the regulation of climacteric fruit ripening.Here,we review and evaluate the complex regulatory network comprising interactions between hormones and the action of TFs and epigenetic modifications during climacteric fruit ripening.展开更多
Epigenetic modifications alter chromatin structures and consequently affect transcription and cellular functions.Major epigenetic markers include DNA methylation and histone acetylation and methylation.The modificatio...Epigenetic modifications alter chromatin structures and consequently affect transcription and cellular functions.Major epigenetic markers include DNA methylation and histone acetylation and methylation.The modifications are reversible and are achieved in aid of relative enzymes.Much effort has been directed at the understanding of the chemical mechanisms of individual catalytic reactions,which can serve as a foundation for inhibitor development.Among the many methods deployed,structural studies have proven the most effective for understanding enzyme-mediated modifications and have provided support for the development of lead-candidate drug inhibitors.This review briefly summarizes the existing knowledge on the catalytic mechanisms of the major epigenetic modification enzymes,with an emphasis on the structural information and inhibitors of these enzymes.展开更多
Alzheimer’s disease(AD)is the most common neurodegenerative disorder affecting the elderly people.AD is characterized by progressive and gradual decline in cognitive function and memory loss.While familial early-onse...Alzheimer’s disease(AD)is the most common neurodegenerative disorder affecting the elderly people.AD is characterized by progressive and gradual decline in cognitive function and memory loss.While familial early-onset AD is usually associated with gene mutations,the etiology of sporadic late-onset form of AD is largely unknown.It has been reported that environmental factors and epigenetic alterations significantly contribute to the process of AD.Our previous studies have documented that chronic hypoxia is one of the environmental factors that may trigger the AD development and aggravate the disease progression.In this review,we will summarize the pathological effects of chronic hypoxia on the onset and development of AD and put forward the possible molecule mechanisms underlying the chronic hypoxia mediated AD pathogenesis.Finally,we propose that epigenetic regulations may represent new opportunity for the therapeutic intervention of this disease.展开更多
How cells sense and respond to environmental changes is still a key question.It has been identified that cellular metabolism is an important modifier of various epigenetic modifications,such as DNA methylation,histone...How cells sense and respond to environmental changes is still a key question.It has been identified that cellular metabolism is an important modifier of various epigenetic modifications,such as DNA methylation,histone methylation and acetylation and RNA N6-methyladenosine(m6A)methylation.This closely links the environmental nutrient availability to the maintenance of chromatin structure and gene expression,and is crucial to regulate cellular homeostasis,cell growth and differentiation.Cancer metabolic reprogramming and epigenetic alterations are widely observed,and facilitate cancer development and progression.In cancer cells,oncogenic signaling-driven metabolic reprogramming modifies the epigenetic landscape via changes in the keymetabolite levels.In this review,we briefly summarized the current evidence that the abundance of key metabolites,such as S-adenosyl methionine(SAM),acetyl-CoA,α-ketoglutarate(α-KG),2-hydroxyglutarate(2-HG),uridine diphospho-N-acetylglucosamine(UDP-GlcNAc)and lactate,affected by metabolic reprogramming plays an important role in dynamically regulating epigenetic modifications in cancer.An improved understanding of the roles of metabolic reprogramming in epigenetic regulation can contribute to uncover the underlying mechanisms of metabolic reprogramming in cancer development and identify the potential targets for cancer therapies.展开更多
Increasing evidence has demonstrated that abnormal epigenetic modifications are strongly related to cancer initiation.Thus,sensitive and specific detection of epigenetic modifications could markedly improve biological...Increasing evidence has demonstrated that abnormal epigenetic modifications are strongly related to cancer initiation.Thus,sensitive and specific detection of epigenetic modifications could markedly improve biological investigations and cancer precision medicine.A rapid development of molecular imaging approaches for the diagnosis and prognosis of cancer has been observed during the past few years.Various biomarkers unique to epigenetic modifications and targeted imaging probes have been characterized and used to discriminate cancer from healthy tissues,as well as evaluate therapeutic responses.In this study,we summarize the latest studies associated with optical molecular imaging of epigenetic modification targets,such as those involving DNA methylation,histone modification,noncoding RNA regulation,and chromosome remodeling,and further review their clinical application on cancer diagnosis and treatment.Lastly,we further propose the future direc-tions for precision imaging of epigenetic modification in cancer.Supported by promising clinical and preclinical studies associated with optical molecular imaging technology and epigenetic drugs,the central role of epigenetics in cancer should be increasingly recognized and accepted.展开更多
Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications wit...Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.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
Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at ma...Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at many levels including nutrient intake,absorption,utilization,and excretion,and can lead to many nutritional disturbances and deficiencies.Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease(ALD).There is growing interest regarding epigenetic changes,including histone modifications that regulate gene expression during disease pathogenesis.Notably,modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation,and control gene transcription.This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD.The review is focused on four critical metabolites,namely,acetate,S-adenosylmethionine,nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD.展开更多
Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediate...Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediated epigenetic processes in the development of cardio-cerebrovascular injury. HDACs are a family of enzymes to balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. To date, 18 mammalian HDACs are identified and grouped into four classes based on similarity to yeast orthologs. The zinc-dependent HDAC family currently consists of 11 members divided into three classes （class I, II, and IV） on the basis of structure, sequence homology, and domain organization. In comparison, class III HDACs （also known as the sirtuins） are composed of a family of NAD＋-dependent protein-modifying enzymes related to the Sir2 gene. HDAC inhibitors are a group of compounds that block HDAC activities typically by binding to the zinc-containing catalytic domain of HDACs and have displayed an- ti-inflammatory and antifibrotic effects in the cardio-cerebrovascular system. In this review, we summarize the current knowledge about classifications, functions of HDACs and their roles and regulatory mechanisms in the cardio-cerebrovascular system. Pharmacological tar- geting of HDAC-mediated epigenetic processes may open new therapeutic avenues for the treatment of CCVD.展开更多
The sea cucumber, Apostichopusjaponicus, undergoes aestivation to improve survival during periods of high-temperature. During aestivation, the metabolic rate is depressed to reduce the consumption of reserved energy. ...The sea cucumber, Apostichopusjaponicus, undergoes aestivation to improve survival during periods of high-temperature. During aestivation, the metabolic rate is depressed to reduce the consumption of reserved energy. We evaluated the role of epigenetic modification on global gene silencing during metabolic rate depression in the sea cucumber. We compared the expression of epigenetic modifiers in active and aestivating sea cucumbers. The expression of three genes involved in DNA methylation and chromatin remodeling （DNA （cytosine-5）-methyltransferase l, Methyl-CpG-binding domain protein 2）, and Chromodomain-helicase-DNA-binding protein 5） was significantly higher during aestivation （Days 20 and 40）. Similarly, we observed an increase in the expression of genes involved in histone acetylation （Histone deacetylase 3） and Histone-binding protein RBBP4） during the early （Days 5 and 10） and late phases （Days 20 and 40） of aestivation. There was no change in the expression of KAT2B, a histone acetyltransferase. However, the expression of histone methylation associated modifiers （Histone-arginine methyltransferase CARMER and Histone-lysine N-methyltransferase MLL5） was significantly higher after 5 d in the aestivating group. The results suggest that the expression of epigenetic modifiers involved in DNA methylation, chromatin remodeling, histone acetylation, and histone methylation is upregulated during aestivation. We hypothesize that these changes regulate global gene silencing during aestivation in A. japonicus.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82271158,82301312,82071045,82101219,82071048).
文摘Hearing loss,which currently affects more than 430 million individuals globally and is projected to exceed 700 million by 2050,predominantly manifests as sensorineural hearing loss(SNHL),for which existing technologies such as hearing aids and cochlear implants fail to restore natural auditory function.Research focusing on protecting inner ear hair cells(HCs)from harmful factors through the regulation of epigenetic modifications has gained significant attention in otology for its role in regulating gene expression without altering the DNA sequence,suggesting potential strategies for preventing and treating SNHL.By synthesizing relevant studies on the inner ear,this review summarizes the emerging roles of histone modifications,DNA methylation,and noncoding RNAs in HC damage,with a focus on their therapeutic potential through epigenetic modulation.Moreover,this review examines the therapeutic potential of epigenetic regulation for the prevention and treatment of SNHL,emphasizing the application of small-molecule epigenetic compounds and their efficacy in modulating gene expression to preserve and restore auditory function.
文摘BACKGROUND Pancreatic cancer(PC)is one of the deadliest malignancies with an alarming mortality rate.Despite significant advancement in diagnostics and therapeutics,early diagnosis remains elusive causing poor prognosis,marred by mutations and epigenetic modifications in key genes which contribute to disease progression.AIM To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley.METHODS A total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9(CA 19-9),tissue polypeptide specific antigen(TPS),carcinoembryonic antigen(CEA),vascular endothelial growth factor-A(VEGF-A),and epidermal growth factor receptor(EGFR).Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma(KRAS),Breast cancer type 2(BRCA-2),and deleted in pancreatic cancer-4(DPC-4)genes.However,epigenetic modifications(methylation of CpG islands)were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A(p16;CDKN2A),MutL homolog 1(hMLH1),and Ras association domain-containing protein 1(RASSF1A)genes.RESULTS We found significantly elevated levels of biological markers CA 19-9(P≤0.05),TPS(P≤0.05),CEA(P≤0.001),and VEGF(P≤0.001).Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12(16 subjects,P≤0.05),and 13(12 subjects,P≤0.05).However,we did not find a mutation in DPC-4(1203G>T)and BRCA-2(617delT)genes.Furthermore,epigenetic modification revealed that CpG methylation in 21(P≤0.05)and 4 subjects in the promoter regions of the p16 and hMLH1 gene,respectively.CONCLUSION In conclusion,CA 19-9,TPS,CEA,and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC.Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC.Additionally,methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.
文摘Background:Retinal pigment epithelium(RPE)is vital for the homeostasis of the subretina including photoreceptors and choroid.Interestingly,our previous results suggested that the recently discovered lactate receptor GPR81 is abundantly expressed in RPE.To date,only one previous study has shown that activating GPR81 could enhance DNA repair by activating HDAC1.Consequently,we investigated whether GPR81 exhibits epigenetic modification in the subretina by using GPR81−/−mice.Methods:GPR81−/−mice and wide type littermates were generated on a background of C57BL/6J mice.The thicknesses of their choroid were evaluated by immunohistochemistry.Meanwhile,Q-PCR,western blot and choroid sprout assay were performed.In vitro,primary retinal pigment epithelium(pRPE)cells were isolated from mice,and cultured for treatments.Results:The thickness of choroid was reduced in GPR81−/−mice compared to GPR81+/+mice,suggesting that GPR81 is important for the integrity of choroid.In the choroid sprout assay,lactate treated RPE/choroid complex showed a significant increase in angiogenesis compared to controls while lactate treated KO RPE/choroid complex showed no difference compared to their controls.For Q-PCR,most of the genes screened elevated their expression in GPR81−/−mice compared to WT mice,suggesting epigenetic modification may exist,which were confirmed by histone acetylation and HDACs activity assay.Conclusions:Taking together,the lactate receptor GPR81 in RPE is very important for maintaining homeostasis of the subretina.This novel discovery sheds new light on the relationship between metabolism and epigenetic modification.
基金This work is funded by National Natural Science Foundation of China(No.81773466)to W.H,and by Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular Disease(No.DXWL2023-06)to W.X.
文摘Epigenetic modifications modulate conformational structure of chromatin and consequently gene expression by enzyme-mediated chemical modifications of DNA and histones.The activities of epigenetic modifying enzymes depend on many co-substrates and cofactors,such as 2-oxoglutarate(2-OG),iron,S-adenosylmethionine(SAM),nicotinamide adenine dinucleotide(NAD+),flavin adenine dinucleotide(FAD),and acetyl-CoA.These factors are inter-connecting molecules that integrate cellular nutrient metabolism and redox homeostasis,two key regulators of cell proliferation,cell survival,and cell functions.Dysregulation of such delicate regulatory network has been implicated in many pathological conditions and also been increasingly recognized as an emerging mechanism responsible for environmental pollutant-induced adverse effects.In this review,we first summarize DNA and histone modifying enzymes and their essential factors,then discuss the metabolic sources and the redox regulatory roles of these enzymatic factors,and finally elaborate the mechanisms of how targeting such factors by environmental pollutants influences epigenetic regulation and perturbs cellular functions.
基金supported by the National Natural Science Foundation of China(82130112 and 62402089)the Natural Science Foundation of Sichuan Province(2025ZNSFSC1465)the China Postdoctoral Science Foundation(2023TQ0047 and GZC20230380).
文摘Dear Editor,Epigenetic modifications are regulatory codes that control gene expression and can be stably inherited without alterations in the genomic sequence(Allis and Jenuwein,2016).Numerous studies have demonstrated that epigenetic modifications regulate critical biological processes in plants,such as growth,development,response to environmental stressors,and reproduction(Zhang et al.,2023;Bulgakov,2024).
基金the National Natural Science Foundation of China(grants 32121005 to J.L.,22277028 to Z.L.H.,22437002 to J.L,22467010 to B.L.L.,and 22207026 to W.W.L.)the Innovation Program of Shanghai Municipal Education Commission(grant 2021-01-07-00-02-E00104 to J.L.)+3 种基金the Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism(grant 2021 Sci&Tech 03-28 to J.L.)the Innovative Research Team of High-level Local Universities in Shanghai(grant SHSMU-ZDCX20212702 to J.L.)the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering(2060204 to J.L.)the innovative research project of graduate students in Hainan Province(SA2400003375 to L.S.)。
文摘Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention.Mitochondrial malate dehydrogenase(MDH2),an enzyme in the TCA cycle,was identified as an anti-aging target through activity-based protein profiling in present study.The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts.Glibenclamide(Gli),a classic anti-glycemic drug,was found to inhibit the activity of MDH2 and relieve fibroblast senescence in an MDH2-dependent manner.The anti-aging effects of Gli were also further validated in vivo,as it extended the lifespan and reduced the frailty index of naturally aged mice.Liver specific Mdh2 knockdown eliminated Gli’s beneficial effects in naturally aged mice,reducing p^(16INK4a) expression and hepatic fibrosis.Mechanistically,MDH2 inhibition or knockdown disrupted central carbon metabolism,then enhanced the methionine cycle flux,and subsequently promoted histone methylation.Notably,the tri-methylation of H3K27,identified as a crucial methylation site in reversing cellular senescence,was significantly elevated in hepatic tissues of naturally aged mice with Mdh2 knockdown.Taken together,these findings reveal that MDH2 inhibition or knockdown delays the aging process through metabolic-epigenetic regulation.Our research not only identified MDH2 as a potential therapeutic target and Gli as a lead compound for anti-aging drug development,but also shed light on the intricate interplay of metabolism and epigenetic modifications in aging.
基金supported by the National Natural Science Foundation of China(Grant No.32271220).
文摘Weight regain(WR)is a significant challenge in clinical treatment of obesity after successful weight loss.WR happens frequently after weight loss(WL)by dietary or life style adjustment although it also occurs in WL by bariatric surgery and medications1-3.A general mechanism of WR is“obesity memory”,which refers to a stable gene expression pattern in adipose tissue from obesity.However,the molecular mechanisms underlying obesity memory remain unclear.Recently,Hinte et al.1 reported that obesity memory is mediated by an epigenetic mechanism in adipocytes of adipose tissue in a Nature article.
基金supported by grants from the National Natural Science Foundation of China(NSFC)Programs(32170186,82200618,82173199)Tianjin Science and Technology Commissioner Project(22JCZDJC00490,22JCQ NJC00540,China).
文摘The mucosal barrier is crucial for intestinal homeostasis,and goblet cells are essential for maintaining the mucosal barrier integrity.The proviral integration site for Moloney murine leukemia virus-1(PIM1)kinase regulates multiple cellular functions,but its role in intestinal homeostasis during colitis is unknown.Here,we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models,in the presence of intestinal microbiota.Epithelial PIM1 leads to decreased goblet cells,thus impairing resistance to colitis and colitis-associated colorectal cancer(CAC)in mice.Mechanistically,PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways.Interestingly,PIM1 interacts with histone deacetylase 2(HDAC2)and downregulates its level via phosphorylation,thereby altering the epigenetic profiles of Wnt signaling pathway genes.Collectively,these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis,which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.
基金supported by grants from the Major Projects of Health Science Research Foundation for Middle-Aged and Young Scientist of Fujian Province,China,No.2022ZQNZD01010010the National Natural Science Foundation of China,No.82371390Fujian Province Scientific Foundation,No.2023J01725(all to XC).
文摘The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.
基金supported by the Special Fund for Agro-scientific Research in the Public Interest (Grant No.:201303143) from the Ministry of Agriculture of the People's Republic of China
文摘DNA methylation is one of the main epigenetic phenomena affecting gene expression.It is an important mechanism for the development of embryo,growth and health of animals.As a key nutritional factor limiting the synthesis of protein,methionine serves as the precursor of S-adenosylmethionine(SAM) in the hepatic one-carbon metabolism.The dietary fluctuation of methionine content can alter the levels of metabolic substrates in one-carbon metabolism,e.g.,the SAM,S-adenosylhomocysteine(SAH),and change the expression of genes related to the growth and health of animals by DNA methylation reactions.The ratio of SAM to SAH is called ‘methylation index' but it should be carefully explained because the complexity of methylation reaction.Alterations of methylation in a specific cytosine-guanine(Cp G)site,rather than the whole promoter region,might be enough to change gene expression.Aberrant methionine cycle may provoke molecular changes of one-carbon metabolism that results in deregulation of cellular hemostasis and health problems.The importance of DNA methylation has been underscored but the mechanisms of methionine affecting DNA methylation are poorly understood.Nutritional epigenomics provides a promising insight into the targeting epigenetic changes in animals from a nutritional standpoint,which will deepen and expand our understanding of genes,molecules,tissues,and animals in which methionine alteration influences DNA methylation and gene expression.
基金the National Natural Science Foundation of China(31722047)the Liaoning Revitalization Talents Program(XLYC1802019).
文摘Fruit ripening is a complex developmental process made up of genetically programmed physiological and biochemical activities.It culminates in desirable changes in the structural and textural properties and is governed by a complex regulatory network.Much is known about ethylene,one of the most important metabolites promoting the ripening of climacteric fruits.However,the dynamic interplay between phytohormones also plays an important part.Additional regulatory factors such as transcription factors(TFs)and epigenetic modifications also play vital role in the regulation of climacteric fruit ripening.Here,we review and evaluate the complex regulatory network comprising interactions between hormones and the action of TFs and epigenetic modifications during climacteric fruit ripening.
文摘Epigenetic modifications alter chromatin structures and consequently affect transcription and cellular functions.Major epigenetic markers include DNA methylation and histone acetylation and methylation.The modifications are reversible and are achieved in aid of relative enzymes.Much effort has been directed at the understanding of the chemical mechanisms of individual catalytic reactions,which can serve as a foundation for inhibitor development.Among the many methods deployed,structural studies have proven the most effective for understanding enzyme-mediated modifications and have provided support for the development of lead-candidate drug inhibitors.This review briefly summarizes the existing knowledge on the catalytic mechanisms of the major epigenetic modification enzymes,with an emphasis on the structural information and inhibitors of these enzymes.
基金by research grants from the National Nature Science Foundation(NO.81000541and NO.81171201)by the National Basic Research Program(NO.2011CB510003).
文摘Alzheimer’s disease(AD)is the most common neurodegenerative disorder affecting the elderly people.AD is characterized by progressive and gradual decline in cognitive function and memory loss.While familial early-onset AD is usually associated with gene mutations,the etiology of sporadic late-onset form of AD is largely unknown.It has been reported that environmental factors and epigenetic alterations significantly contribute to the process of AD.Our previous studies have documented that chronic hypoxia is one of the environmental factors that may trigger the AD development and aggravate the disease progression.In this review,we will summarize the pathological effects of chronic hypoxia on the onset and development of AD and put forward the possible molecule mechanisms underlying the chronic hypoxia mediated AD pathogenesis.Finally,we propose that epigenetic regulations may represent new opportunity for the therapeutic intervention of this disease.
基金National Natural Science Foundation of China(91749205,92049302,32088101)China Ministry of Science and Technology(2020YFA0804000,2016YFE0108700)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)to J.D.J.H.The funding organizations played no role in the study design。
文摘How cells sense and respond to environmental changes is still a key question.It has been identified that cellular metabolism is an important modifier of various epigenetic modifications,such as DNA methylation,histone methylation and acetylation and RNA N6-methyladenosine(m6A)methylation.This closely links the environmental nutrient availability to the maintenance of chromatin structure and gene expression,and is crucial to regulate cellular homeostasis,cell growth and differentiation.Cancer metabolic reprogramming and epigenetic alterations are widely observed,and facilitate cancer development and progression.In cancer cells,oncogenic signaling-driven metabolic reprogramming modifies the epigenetic landscape via changes in the keymetabolite levels.In this review,we briefly summarized the current evidence that the abundance of key metabolites,such as S-adenosyl methionine(SAM),acetyl-CoA,α-ketoglutarate(α-KG),2-hydroxyglutarate(2-HG),uridine diphospho-N-acetylglucosamine(UDP-GlcNAc)and lactate,affected by metabolic reprogramming plays an important role in dynamically regulating epigenetic modifications in cancer.An improved understanding of the roles of metabolic reprogramming in epigenetic regulation can contribute to uncover the underlying mechanisms of metabolic reprogramming in cancer development and identify the potential targets for cancer therapies.
基金supported by Beijing Natural Science Foundation under Grant No.7212207,Ministry of Science and Technology of China under Grant No.2017YFA0205200,2017YFA0700401National Natural Science Foundation of China under Grant Nos.81871514,92159303,62027901,81227901,81470083,and 81527805the National Key Research and Development Program of China under Grant 2017YFA0700401.
文摘Increasing evidence has demonstrated that abnormal epigenetic modifications are strongly related to cancer initiation.Thus,sensitive and specific detection of epigenetic modifications could markedly improve biological investigations and cancer precision medicine.A rapid development of molecular imaging approaches for the diagnosis and prognosis of cancer has been observed during the past few years.Various biomarkers unique to epigenetic modifications and targeted imaging probes have been characterized and used to discriminate cancer from healthy tissues,as well as evaluate therapeutic responses.In this study,we summarize the latest studies associated with optical molecular imaging of epigenetic modification targets,such as those involving DNA methylation,histone modification,noncoding RNA regulation,and chromosome remodeling,and further review their clinical application on cancer diagnosis and treatment.Lastly,we further propose the future direc-tions for precision imaging of epigenetic modification in cancer.Supported by promising clinical and preclinical studies associated with optical molecular imaging technology and epigenetic drugs,the central role of epigenetics in cancer should be increasingly recognized and accepted.
基金supported by the National Natural Science Foundation of China,Nos.82071383,82371392(to BN)the Natural Science Foundation of Shandong Province of China(Key Project),No.ZR2020KH007(to BN)+1 种基金“Taishan Scholar Distinguished Expert Program”of Shandong Province,No.tstp20231257(to BN)Health Commission Science and Technology Plan Project of Jinan,No.2023-1-8(to YZ).
文摘Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.
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 Institute of Alcohol Abuse and Alcoholism grants AA014371 (to Joshi-Barve S),AA015970 (to McClain CJ), and Office of Dietary Supplements, NIH
文摘Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at many levels including nutrient intake,absorption,utilization,and excretion,and can lead to many nutritional disturbances and deficiencies.Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease(ALD).There is growing interest regarding epigenetic changes,including histone modifications that regulate gene expression during disease pathogenesis.Notably,modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation,and control gene transcription.This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD.The review is focused on four critical metabolites,namely,acetate,S-adenosylmethionine,nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD.
基金This study was supported by grants from the National 973 Basic Research Program of China，the National Nature Science Foundation of China，Foundation of Program for New Century Excellent Talents in University (NCET-11-0311) to Yi F，Program for Changjiang Scholars and Innovative Research Team in University，the Special Financial Grant from the China Postdoctoral Science Foundation，the China Postdoctoral Science Foundation，the Shandong Province Post-doctoral Innovation Foundation
文摘Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediated epigenetic processes in the development of cardio-cerebrovascular injury. HDACs are a family of enzymes to balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. To date, 18 mammalian HDACs are identified and grouped into four classes based on similarity to yeast orthologs. The zinc-dependent HDAC family currently consists of 11 members divided into three classes （class I, II, and IV） on the basis of structure, sequence homology, and domain organization. In comparison, class III HDACs （also known as the sirtuins） are composed of a family of NAD＋-dependent protein-modifying enzymes related to the Sir2 gene. HDAC inhibitors are a group of compounds that block HDAC activities typically by binding to the zinc-containing catalytic domain of HDACs and have displayed an- ti-inflammatory and antifibrotic effects in the cardio-cerebrovascular system. In this review, we summarize the current knowledge about classifications, functions of HDACs and their roles and regulatory mechanisms in the cardio-cerebrovascular system. Pharmacological tar- geting of HDAC-mediated epigenetic processes may open new therapeutic avenues for the treatment of CCVD.
基金Supported by the National Key Technology Research and Development Program(No.2006AA10A411)the Agricultural Seed Project of Shandong Province
文摘The sea cucumber, Apostichopusjaponicus, undergoes aestivation to improve survival during periods of high-temperature. During aestivation, the metabolic rate is depressed to reduce the consumption of reserved energy. We evaluated the role of epigenetic modification on global gene silencing during metabolic rate depression in the sea cucumber. We compared the expression of epigenetic modifiers in active and aestivating sea cucumbers. The expression of three genes involved in DNA methylation and chromatin remodeling （DNA （cytosine-5）-methyltransferase l, Methyl-CpG-binding domain protein 2）, and Chromodomain-helicase-DNA-binding protein 5） was significantly higher during aestivation （Days 20 and 40）. Similarly, we observed an increase in the expression of genes involved in histone acetylation （Histone deacetylase 3） and Histone-binding protein RBBP4） during the early （Days 5 and 10） and late phases （Days 20 and 40） of aestivation. There was no change in the expression of KAT2B, a histone acetyltransferase. However, the expression of histone methylation associated modifiers （Histone-arginine methyltransferase CARMER and Histone-lysine N-methyltransferase MLL5） was significantly higher after 5 d in the aestivating group. The results suggest that the expression of epigenetic modifiers involved in DNA methylation, chromatin remodeling, histone acetylation, and histone methylation is upregulated during aestivation. We hypothesize that these changes regulate global gene silencing during aestivation in A. japonicus.
