Reader proteins that bind specific methyllysine are important to biological functions of lysine methylation,but readers of many methyllysine sites are still unknown.Therefore,development of covalent probes is importan...Reader proteins that bind specific methyllysine are important to biological functions of lysine methylation,but readers of many methyllysine sites are still unknown.Therefore,development of covalent probes is important to identify readers from cell samples so as to understand biological roles of lysine methylation.Generally,readers bind methyllysine via aromatic cages that contain tryptophan,tyrosine and phenylalanine,that offer a unique motif for selective crosslinking.We recently reported a site-selective tryptophan crosslinking strategy based on dimethylsulfonium that mimics dimethyllysine to crosslink tryptophan in aromatic cages of readers.Since tyrosine is a key residue for binding affinity to methyllysine,especially some readers that do not contain tryptophan residues in the binding pocket.Here we developed strategies of site-selective crosslinking to tyrosine.Ultraviolet(UV)source was applied to excite tyrosine at neutral pH or phenoxide at basic p H,and subsequent single-electron transfer(SET)from Tyr*to sulfonium inside the binding pocket enables selective crosslinking.In consequence,methyllysine readers with tyrosine-containing aromatic cages could be selectively crosslinked by site-specific sulfonium peptide probes.In addition,we expanded substrates from aromatic cages to tyrosine residues of proximate contact with sulfonium probes.The pair of LgBiT and SmBiT exhibited orthogonal crosslinking in complicated cell samples.As a result,we may expand sulfonium tools to target local tyrosine in future investigations.展开更多
Detecting lung cancer early is crucial for improving survival rates,yet it remains a significant challenge due to many cases being diagnosed at advanced stages.This review aims to provide advances in epigenetics which...Detecting lung cancer early is crucial for improving survival rates,yet it remains a significant challenge due to many cases being diagnosed at advanced stages.This review aims to provide advances in epigenetics which have highlighted DNA methylation patterns as promising biomarkers for early detection,prognosis,and treatment response in lung cancer.Techniques like bisulfite conversion followed by PCR,digital droplet polymerase chain reaction,and next-generation sequencing are commonly used for detecting these methylation patterns,which occur early in the cancer development process and can be detected in non-invasive samples like blood and sputum.Key genes such as SHOX2 and RASSF1A have demonstrated high sensitivity and specificity in clinical studies,making them crucial for diagnostic purposes.However,several challenges remain to be overcome before these biomarkers can be widely adopted for use in clinical practice.Standardizing the assays and validating their effectiveness are critical steps.Additionally,integrating methylation biomarkers with existing diagnostic tools could significantly enhance the accuracy of lung cancer detection,providing a more comprehensive diagnostic approach.Although progress has been made in understanding and utilizing DNA methylation patterns for lung cancer detection,more research and extensive clinical trials are necessary to fully harness their potential.These efforts will help establish the robustness of methylation patterns as biomarkers and therapeutic targets,ultimately leading to better prevention,diagnosis,and treatment strategies for lung cancer.In conclusion,DNA methylation states represent a promising avenue for advancing early detection,accurate diagnosis,and management of lung cancer.展开更多
The methylation of DNA is a prevalent epigenetic modification that plays a crucial role in the pathological progression of ocular diseases.DNA methylation can regulate gene expression,thereby affecting cell function a...The methylation of DNA is a prevalent epigenetic modification that plays a crucial role in the pathological progression of ocular diseases.DNA methylation can regulate gene expression,thereby affecting cell function and signal transduction.Ophthalmic diseases are a kind of complex diseases,and their pathogenesis involves many factors such as genetic,environmental and individual differences.In addition,inflammation,oxidative stress and lipid metabolism,which abnormal DNA methylation is closely related to,are also considered to be major factors in eye diseases.The current understanding of DNA methylation in eye diseases is becoming more complex and comprehensive.In addition to the simple suppression of gene expression by hypermethylation,factors such as hypomethylation or demethylation,DNA methylation in non-promoter regions,interactions with other epigenetic modifications,and dynamic changes in DNA methylation must also be considered.Interestingly,although some genes are at abnormal methylation levels,their expression is not significantly changed,which indirectly reflects the complexity of gene regulation.This review aims to summarize and compare some relevant studies,and provide with new ideas and methods for the prevention and treatment of different eye diseases,such as glaucoma,retinoblastoma,and diabetic retinopathy.展开更多
Illegal hunting and trafficking of wildlife and their derivatives extort unprecedented population decline of relatively many species pushing them towards extinction.Notwithstanding contemporary counteracting intervent...Illegal hunting and trafficking of wildlife and their derivatives extort unprecedented population decline of relatively many species pushing them towards extinction.Notwithstanding contemporary counteracting interventions at international,regional,national and local levels,wildlife farming is advocated as an alternative approach to minimize pressure on wild populations.For wildlife farming to be an effective conservation tool,the integration of wildlife forensics is inevitable to allow distinction between captive-bred and wild-caught species.To this end,we analyzed methylation rates of skeletal muscle samples(pectoralis major,triceps brachii,gastrocnemius,biceps femoris,and neck muscles)from 60 captive-bred and 30 wild-caught Common Pheasant.A total of 13,507 differentially methylated regions were identified between five wild-caught and five captive-bred individuals through whole-genome methylation sequencing(WGBS).Based on the selected five methylation sites,LOC116231076,LOC116242223,ATAD2B,EGFL6,and HS2ST,quantitative detection technique was developed using methylation-sensitive high-resolution melting curve(MS-HRM)to measure methylation rates.The results showed significant differences in methylation rates at all differential sites between wild-caught and captive-bred individuals(|t|=0.67–33.10,P=0.000–0.042).The discrimination accuracy rate of each locus was highest in the gastrocnemius muscle and lowest in the neck muscle.The discrimination accuracy rate on LOC116231076,LOC116242223,ATAD2B,EGFL6,and HS2ST methylation sites for gastrocnemius muscle was 64.98%,100.00%,68.54%,63.79%,and 63.70%,respectively;and for neck muscle it was 67.42%,68.06%,83.61%,65.04%,and68.85%,respectively.The united discrimination accuracy rate of the five loci were 100.00%for gastrocnemius muscle,99.78%for biceps femoris muscle,97.52%for pectoralis major muscle,93.96%for triceps brachii muscle,and 91.63%for neck muscle,respectively.The panel also revealed excellent repeatability,reproducibility,sensitivity and universality to mammals and avian species.This study establishes an effective,accurate and low-cost identification technology for the identification of wild and farmed Common Pheasant,and also provides a reference for the development of identification methods for other species.展开更多
BACKGROUND Gastric cancer(GC)is a malignant tumor originating from gastric mucosal epithelial cells that has high morbidity and mortality.microRNAs(miR)are important diagnostic markers and therapeutic targets in this ...BACKGROUND Gastric cancer(GC)is a malignant tumor originating from gastric mucosal epithelial cells that has high morbidity and mortality.microRNAs(miR)are important diagnostic markers and therapeutic targets in this disease.AIM To explore the mechanism of miR-125a-5p in the pathogenesis of GC.METHODS The expression levels of miR-125a-5p,SERPINE1 and DNMT1 in GC cells and tissues were detected by real-time polymerase chain reaction(PCR)and Western blotting.Methylation-specific PCR was used to detect the level of miR-125a-5p methylation.A cell counting kit 8 assay,scratch test,and a Transwell assay were performed to detect the proliferation,migration,and invasiveness of HGC27 cells,respectively.The expression of the epithelial mesenchymal transition(EMT)-related proteins E-cadherin,N-cadherin and vimentin in HGC27 cells was detected by Western blotting,while the expression of vimentin was detected by immunofluorescence.RESULTS This study revealed that miR-125a-5p was expressed at low levels in GC clinical samples and cells and that miR-125a-5p overexpression inhibited the proliferation,migration,invasiveness and EMT of GC cells.Mechanistically,miR-125a-5p can reduce GC cell proliferation,promote E-cadherin expression,inhibit N-cadherin and vimentin expression,and reduce the EMT of GC cells,thus constraining GC cells to a certain extent.Moreover,DNMT1 inhibited miR-125a-5p expression by increasing the methylation of the miR-125a-5p promoter,thereby promoting the expression of SERPINE1,which acts together with miR-125a-5p to exert antagonistic effects on GC.CONCLUSION Our study revealed that DNMT1 promoted SERPINE1 protein expression by inducing miR-125a-5p methylation,which led to the proliferation,migration and occurrence of EMT in GC cells.展开更多
BACKGROUND Epigenetic regulation of leptin(LEP)plays a critical role in metabolic disorders,yet its promoter methylation patterns in lean diabetic populations remain poorly characterized.Emerging evidence suggests DNA...BACKGROUND Epigenetic regulation of leptin(LEP)plays a critical role in metabolic disorders,yet its promoter methylation patterns in lean diabetic populations remain poorly characterized.Emerging evidence suggests DNA methylation may precede clinical hyperglycemia,offering potential for early risk stratification.While obesity-associated LEP methylation is well-studied,lean Asian populations who exhibit high diabetes prevalence despite lower adiposity,represent an underexplored cohort.This study hypothesizes that LEP promoter methylation in peripheral leukocytes decreases progressively from normoglycemia to prediabetes and type 2 diabetes mellitus(T2DM),correlating inversely with serum LEP levels in lean Chinese adults[body mass index(BMI)<24 kg/m^(2)].AIM To investigate LEP promoter methylation status and its association with serum LEP levels across glycemic states in lean Chinese adults.METHODS We enrolled 392 participants including 120 normoglycemic controls,94 prediabetes[44 impaired fasting glucose(IFG)/50 impaired glucose tolerance(IGT)],178 T2DM aged 40-60 years with BMI<24 kg/m^(2).Genomic DNA from peripheral leukocytes underwent bisulfite conversion followed by methylation-specific PCR to assess CpG methylation in the LEP promoter.Serum LEP was quantified via enzyme-linked immunosorbent assay,with other parameters measured through standard assays.Statistical analyses included analysis of variance,χ²tests,and Pearson correlation(Bonferroni-corrected P value).RESULTS Methylation frequencies declined progressively:59.2%(controls)reduced to 43.6%(prediabetes;IFG:38.6%,IGT:48%)reduced to 31.5%(T2DM)(all P<0.05 vs controls;T2DM vs IGT:P=0.030).Serum LEP levels increased significantly in T2DM(16.94±4.19μg/L)vs controls(11.33±3.10μg/L;P=0.002),with intermediate values in prediabetes(IFG:13.79±3.32μg/L;IGT:12.62±4.81μg/L).A near-perfect inverse correlation between methylation and LEP levels was observed(r=-0.95,95%CI:-0.97 to-0.92,P<0.001),persisting after adjusting for age and BMI(β=-0.91,P<0.001).CONCLUSION LEP promoter hypomethylation parallels worsening glycemic status in lean Chinese adults,suggesting its potential as a blood-based epigenetic biomarker for diabetes progression,pending validation in longitudinal cohorts.展开更多
Cyclic volatile methyl siloxanes(cVMSs)are widely used in industrial and consumer products because of their thermal stability,low reactivity,and reduced surface tension[1].Their extensive use has resulted in environme...Cyclic volatile methyl siloxanes(cVMSs)are widely used in industrial and consumer products because of their thermal stability,low reactivity,and reduced surface tension[1].Their extensive use has resulted in environmental pollution globally.Recognized as very persistent and very bioaccumulative(vPvB),compounds such as octamethylcyclotetrasiloxane(D4),decamethylcyclopentasiloxane(D5),and dodecamethylcyclohexasiloxane(D6)are regulated in the European Union[2]and are monitored worldwide.展开更多
In the mammalian genome,most CpGs are methylated.However,CpGs within the CpG islands(CGIs)are largely unmethylated,which are important for gene expression regulation.The mechanism underlying the low methylation levels...In the mammalian genome,most CpGs are methylated.However,CpGs within the CpG islands(CGIs)are largely unmethylated,which are important for gene expression regulation.The mechanism underlying the low methylation levels at CGIs remains largely elusive.KDM2 proteins(KDM2A and KDM2B)are H3K36me2 demethylases known to bind specifically at CGIs.Here,we report that depletion of each or both KDM2 proteins,or mutation of all their JmjC domains that harbor the H3K36me2 demethylation activity,leads to an increase in DNA methylation at selective CGIs.The Kdm2a/2b double knockout shows a stronger increase in DNA methylation compared with the single mutant of Kdm2a or Kdm2b,indicating that KDM2A and KDM2B redundantly regulate DNA methylation at CGIs.In addition,the increase of CGI DNA methylation upon mutations of KDM2 proteins is associated with the chromatin environment.Our findings reveal that KDM2A and KDM2B function redundantly in regulating DNA methylation at a subset of CGIs in an H3K36me2 demethylation-dependent manner.展开更多
DNA methylation is a critical epigenetic regulator in the occurrence and development of diseases and is closely related to various functional responses in relation to spinal cord injury.To investigate the role of DNA ...DNA methylation is a critical epigenetic regulator in the occurrence and development of diseases and is closely related to various functional responses in relation to spinal cord injury.To investigate the role of DNA methylation in spinal cord injury,we constructed a library with reduced-representation bisulfite sequencing data obtained at various time points(day 0-42)after spinal cord injury in mice.Global DNA methylation levels,specifically non-CpG(CHG and CHH)methylation levels,decreased modestly following spinal cord injury.Stages post-spinal cord injury were classified as early(day 0-3),intermediate(day7-14),and late(day 28-42)based on similarity and hie rarchical cluste ring of global DNA methylation patterns.The non-CpG methylation level,which included CHG and CHH methylation levels,was markedly reduced despite accounting for a minor proportion of total methylation abundance.At multiple genomic sites,including the 5’untranslated regions,promoter,exon,intron,and 3’untranslated regions,the non-CpG methylation level was markedly decreased following spinal cord injury,whereas the CpG methylation level remained unchanged at these locations.Approximately one-half of the differentially methylated regions were located in intergenic areas;the other differentially methylated regions in both CpG and non-CpG regions were cluste red in intron regions,where the DNA methylation level was highest.The function of genes associated with differentially methylated regions in promoter regions was also investigated.From Gene Ontology analysis results,DNA methylation was implicated in a number of essential functional responses to spinal cord injury,including neuronal synaptic connection creation and axon regeneration.Notably,neither CpG methylation nor non-CpG methylation was implicated in the functional response of glial or inflammatory cells.In summary,our work elucidated the dynamic pattern of DNA methylation in the spinal co rd following injury and identified reduced nonCpG methylation as an epigenetic target after spinal cord injury in mice.展开更多
Colitis-associated colorectal cancer(CAC),a serious complication of ulcerative colitis(UC),is associated with a poor prognosis.The vitamin D receptor(VDR)is recognized for its protective role in UC and CAC through the...Colitis-associated colorectal cancer(CAC),a serious complication of ulcerative colitis(UC),is associated with a poor prognosis.The vitamin D receptor(VDR)is recognized for its protective role in UC and CAC through the maintenance of intestinal barrier integrity and the regulation of inflammation.This study demonstrates a significant reduction in m^(6)A-related genes,particularly methyltransferase like 14(METTL14),in UC and CAC patients and identifies an association between METTL14 and VDR.In the azoxymethane(AOM)/dextran sodium sulfate(DSS)-induced mousemodel,vitamin D treatment increases METTL14 expression and reduces tumorburden,while Vdr-knockout mice exhibit lower METTL14 levels and increased tumorigenesis.In vitro,the VDR agonist calcipotriol upregulates METTL14 in NCM460 cells,with this effect attenuated by VDR knockdown.VDRknockdown inDLD-1colon cancer cellsdecreases METTL14 expressionand promotes proliferation,which is reversed by METTL14 overexpression.Mechanistic studies reveal that VDR regulates METTL14 expression via promoter binding,modulating key target genes such as SOX4,DROSH,and PHLPP2.This study highlights the role of the VDR-METTL14 axis as a protective mechanism in CAC and suggests its potential as a therapeutic target for preventing and treating CAC.展开更多
Homoisoflavonoids are in the subclass of the larger family of flavonoids having one more alkyl carbon than flavonoids. Among them, 8-C-Methylated homoisoflavones have not been extensively studied for synthesis and bio...Homoisoflavonoids are in the subclass of the larger family of flavonoids having one more alkyl carbon than flavonoids. Among them, 8-C-Methylated homoisoflavones have not been extensively studied for synthesis and biological evaluation. Author’s current objective is to synthesize 8-C-Methylated homoisoflavones by the reaction of 3-C-methylated dihydrochalcones with N,N’-dimethyl (chloromethylene) ammonium chloride generated in situ from DMF and PCl<sub>5</sub> for one carbon extension at about room temperature. The 3-C-methylated dihydrochalcones were synthesized by the reduction of 3-C-methylated chalcones, which were prepared from 3-C-methylated acetophenones and aromatic aldehydes in the presence of base. All the synthesized novel homoisoflavones’s structures were characterized by NMR and Tandem Mass Spectrometry.展开更多
Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environme...Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.展开更多
RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species-specific. However, people rarely know their biological func...RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species-specific. However, people rarely know their biological functions. There are several identified methylation modifications in eukaryotic messenger RNA （mRNA）, such as NT-methylguanosine （mVG） at the cap, Nr-methyl-2＇-O-methyladenosine （m6Am）, 2＇-O-methylation （Nm） within the cap and the internal positions, and internal N6-methyladenosine （m6A） and 5-methylcytosine （mSC）. Among them, mTG cap was studied more clearly and found to have vital roles in several important mRNA processes like mRNA translation, stability and nuclear export, m6A as the most abundant modification in mRNA was found in the 1970s and has been proposed to function in mRNA splicing, translation, stability, transport and so on. mrA has been discovered as the first RNA reversible modification which is demethylated directly by human fat mass and obesity associated protein （FRO） and its homolog protein, alkylation repair ho- molog 5 （ALKBH5）. b-TO has a special demethylation mechanism that demethylases m6A to A through two over-oxidative intermediate states： N6-hydroxymethyladenosine （hm6A） and Nr-formyladenosine （frA）. The two newly discovered m6A demethylases, bTO and ALKBH5, significantly control energy homeostasis and spermatogenesis, respectively, indicating that the dynamic and reversible mrA, analogous to DNA and histone modifications, plays broad roles in biological kingdoms and brings us an emerging field ＂RNA Epige- netics＂. 5-methylcytosine （5mC） as an epigenetic mark in DNA has been studied widely, but mSC in mRNA is seldom explored. The bisulfide sequencing showed mSC is another abundant modification in mRNA, suggesting that it might be another RNA epigenetic mark. This review focuses on the main methylation modifications in mRNA to describe their formation, distribution, function and demethylation from the current knowledge and to provide future 19erspectives on functional studies.展开更多
Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulatio...Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target.Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails.Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients.Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies.Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance.Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions,and novel pharmacological strategies that target these components could potentially lead to breakthroughs.We aim to highlight the possibilities that exist and the potential therapeutic interventions.展开更多
BACKGROUND Cholangiocarcinoma(CCA),also known as bile duct cancer,is a devastating malignancy primarily affecting the biliary tract.AIM To assess their performance in clinical diagnosis and monitoring of CCA,plasma me...BACKGROUND Cholangiocarcinoma(CCA),also known as bile duct cancer,is a devastating malignancy primarily affecting the biliary tract.AIM To assess their performance in clinical diagnosis and monitoring of CCA,plasma methylation and circulating tumor cells were detected.METHODS Plasma samples were collected from Hubei Cancer Hospital(n=156).Plasma DNA was tested to detect SHOX2,HOXA9,SEPTIN9,and RASSF1A methylation using TaqMan PCR.Circulating tumor cells(CTCs)were detected in the peripheral blood of patients using the United States Food and Drug Administration-approved cell search system before and after clinical therapy.The CCA diagnostic value was estimated using the area under the curve.The independent prognosis risk factors for patients with CCA were estimated using Cox and logistic regression analyses.RESULTS The sensitivity and specificity of the four DNA plasma methylations exhibited 64.74%sensitivity and 93.88%specificity for detecting CCA.The receiver operating characteristic curve of the combined value for CCA diagnosis in plasma was 0.828±0.032.RASSF1A plasma methylation was related to the prognosis of patients with CCA.We determined the prognostic hazard ratio for CCA using CTC count,tumor stage,methylation,and carbohydrate antigen 19-9 levels as key factors.Our overall survival nomogram achieved a C-index of 0.705(0.605-0.805).CONCLUSION SHOX2,HOXA9,SEPTIN9,and RASSF1A plasma methylation demonstrated increased sensitivity for diagnosing CCA.RASSF1A plasma methylation and CTCs were valuable predictors to assess CCA prognosis and recurrence.展开更多
DNA methylation plays important roles in regulating gene expression during development.However,little is known about the influence of DNA methylation on secondary metabolism during leaf development in the tea plant(Ca...DNA methylation plays important roles in regulating gene expression during development.However,little is known about the influence of DNA methylation on secondary metabolism during leaf development in the tea plant(Camellia sinensis).In this study,we combined the methylome,transcriptome,and metabolome to investigate the dynamic changes in DNA methylation and its potential regulatory roles in secondary metabolite biosynthesis.In this study,the level of genomic DNA methylation increased as leaf development progressed from tender to old leaf.It additionally exhibited a similar distribution across the genomic background at the two distinct developmental stages studied.Notably,integrated analysis of transcriptomic and methylomic data showed that DNA hypermethylation primarily occurred in genes of the phenylpropanoid,flavonoid,and terpenoid biosynthesis pathways.The effect of methylation on transcription of these secondary metabolite biosynthesis genes was dependent on the location of methylation(i.e.,in the promoter,gene or intergenic regions)and the sequence context(i.e.,CpG,CHG,or CHH).Changes in the content of catechins and terpenoids were consistent with the changes in gene transcription and the methylation state of structural genes,such as serine carboxypeptidase-like acyltransferases 1A(SCPL1A),leucoanthocyanidin reductase(LAR),and nerolidol synthase(NES).Our study provides valuable information for dissecting the effects of DNA methylation on regulation of genes involved in secondary metabolism during tea leaf development.展开更多
Arsenic(As)methylation in soils affects the environmental behavior of As,excessive accumulation of dimethylarsenate(DMA)in rice plants leads to straighthead disease and a serious drop in crop yield.Understanding the m...Arsenic(As)methylation in soils affects the environmental behavior of As,excessive accumulation of dimethylarsenate(DMA)in rice plants leads to straighthead disease and a serious drop in crop yield.Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security.Here,soils including unarsenic contaminated(N-As),low-arsenic(L-As),medium-arsenic(M-As),and high-arsenic(H-As)soils were incubated under continuous anoxic,continuous oxic,and consecutive anoxic/oxic treatments respectively,to profile arsenic methylating process and microbial species involved in the As cycle.Under anoxic-oxic(A-O)treatment,methylated arsenic was significantly increased once oxygen was introduced into the incubation system.The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic(A),oxic(O),and oxic-anoxic(O-A)treatments,under which arsenic was methylated slightly and then decreased in all four As concentration soils.In fact,the most plentiful arsenite S-adenosylmethionine methyltransferase genes(arsM)contributed to the increase in As methylation.Proteobacteria(40.8%-62.4%),Firmicutes(3.5%-15.7%),and Desulfobacterota(5.3%-13.3%)were the major microorganisms related to this process.These microbial increasedmarkedly and played more important roles after oxygen was introduced,indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic(flooding)and oxic(drainage)environment.The novel findings provided newinsights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.展开更多
BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge...BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge.Fear conditioning and extinction in animal models offer insights into its mechanisms.Our previous research indi-cates that DNA methyltransferases play a role in fear memory renewal.AIM To investigate the role of DNA methylation in the extinction of fear memory,with the goal of identifying potential strategies to enhance the efficacy of exposure therapy for fear-related disorders.METHODS This study investigated the role of DNA methylation in fear memory extinction in mice.DNA methylation was manipulated using N-phthalyl-L-tryptophan(RG108)to reduce methylation and L-methionine injections to enhance it.Neuronal activity,and dendritic spine density was measured following extinction training.RESULTS RG108 suppressed extinction,reduced spine density,and inhibited neuronal activity.Methionine injections facilitated extinction.CONCLUSION DNA methylation is crucial for fear memory extinction.Enhancing methylation may improve the efficacy of exposure therapy,offering a potential strategy to treat fear-related disorders.展开更多
Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This s...Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This study demonstrates that tenacissoside I(TI),a compound isolated from Marsdenia tenacissima(Roxb.)Wight et Arn,traditionally used in clinical practice as an ethnic medicine for cancer treatment,exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells.TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin(DOX)and paclitaxel(PAC)by downregulating ABCB1 expression and reducing ABCB1 drug transport function.Mechanistically,protein arginine methyltransferase 1(PRMT1),whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues,was differentially expressed in TI-treated SW620/AD300 cells.SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine(aDMA)and enhanced PRMT1-EGFR interaction compared to their parental cells.Moreover,TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR,PRMT1-EGFR interaction,and EGFR downstream signaling in SW620/AD300 and KBV200 cells.These effects were significantly reversed by PRMT1 overexpression.Additionally,TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities.This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR,suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.展开更多
Background N^(6)-methyladenosine(m^(6)A)methylation is a key epigenetic modification that can modulate gene expression and strongly affect mammalian developmental processes.However,the genome-wide methylation of long ...Background N^(6)-methyladenosine(m^(6)A)methylation is a key epigenetic modification that can modulate gene expression and strongly affect mammalian developmental processes.However,the genome-wide methylation of long non-coding RNAs(lncRNAs)and its implications for the development of skeletal muscle remain poorly understood.Bovine skeletal muscle samples from five developmental stages were analyzed in this study to establish lncRNA methylome and transcriptomic maps.Results Globally,59.67%of lncRNAs in skeletal muscle with m^(6)A modifications,and this percentage decreased progressively during development.lncRNA expression levels were positively associated with the number of m^(6)A peaks,with lncRNAs possessing 3 or more peaks showing significantly higher expression levels than those with 1 or 2 peaks.Specific lncRNAs involved in skeletal muscle development were identified through two analytical approaches.The first approach employed weighted gene co-expression network analysis(WGCNA)of transcriptomic data to identify correlations between annotated lncRNAs and growth-related traits,resulting in 21 candidate hub lncRNAs.The intersection of these 21 hub lncRNAs with 151 differentially methylated lncRNAs(DM-lncRNAs)identified 10 shared candidate lncRNAs.The second approach integrated MeRIP-seq and RNA-seq data to identify 36 lncRNAs that were both differentially m^(6)A modified and differentially expressed(dme-lncRNAs).GO and KEGG enrichment analyses of cis-target genes associated with these dme-lncRNAs identified eight candidate lncRNAs.Combining the results from the two approaches identified 16 key m^(6)A-modified lncRNAs likely involved in skeletal muscle development.Conclusions These findings highlight the regulatory and functional significance of dynamic lncRNA methylation in skeletal muscle development.展开更多
基金the support from National Natural Science Foundation of China(No.22161132006)Key R&D Program of Zhejiang(No.2024SSYS0036)Westlake University Startup。
文摘Reader proteins that bind specific methyllysine are important to biological functions of lysine methylation,but readers of many methyllysine sites are still unknown.Therefore,development of covalent probes is important to identify readers from cell samples so as to understand biological roles of lysine methylation.Generally,readers bind methyllysine via aromatic cages that contain tryptophan,tyrosine and phenylalanine,that offer a unique motif for selective crosslinking.We recently reported a site-selective tryptophan crosslinking strategy based on dimethylsulfonium that mimics dimethyllysine to crosslink tryptophan in aromatic cages of readers.Since tyrosine is a key residue for binding affinity to methyllysine,especially some readers that do not contain tryptophan residues in the binding pocket.Here we developed strategies of site-selective crosslinking to tyrosine.Ultraviolet(UV)source was applied to excite tyrosine at neutral pH or phenoxide at basic p H,and subsequent single-electron transfer(SET)from Tyr*to sulfonium inside the binding pocket enables selective crosslinking.In consequence,methyllysine readers with tyrosine-containing aromatic cages could be selectively crosslinked by site-specific sulfonium peptide probes.In addition,we expanded substrates from aromatic cages to tyrosine residues of proximate contact with sulfonium probes.The pair of LgBiT and SmBiT exhibited orthogonal crosslinking in complicated cell samples.As a result,we may expand sulfonium tools to target local tyrosine in future investigations.
文摘Detecting lung cancer early is crucial for improving survival rates,yet it remains a significant challenge due to many cases being diagnosed at advanced stages.This review aims to provide advances in epigenetics which have highlighted DNA methylation patterns as promising biomarkers for early detection,prognosis,and treatment response in lung cancer.Techniques like bisulfite conversion followed by PCR,digital droplet polymerase chain reaction,and next-generation sequencing are commonly used for detecting these methylation patterns,which occur early in the cancer development process and can be detected in non-invasive samples like blood and sputum.Key genes such as SHOX2 and RASSF1A have demonstrated high sensitivity and specificity in clinical studies,making them crucial for diagnostic purposes.However,several challenges remain to be overcome before these biomarkers can be widely adopted for use in clinical practice.Standardizing the assays and validating their effectiveness are critical steps.Additionally,integrating methylation biomarkers with existing diagnostic tools could significantly enhance the accuracy of lung cancer detection,providing a more comprehensive diagnostic approach.Although progress has been made in understanding and utilizing DNA methylation patterns for lung cancer detection,more research and extensive clinical trials are necessary to fully harness their potential.These efforts will help establish the robustness of methylation patterns as biomarkers and therapeutic targets,ultimately leading to better prevention,diagnosis,and treatment strategies for lung cancer.In conclusion,DNA methylation states represent a promising avenue for advancing early detection,accurate diagnosis,and management of lung cancer.
文摘The methylation of DNA is a prevalent epigenetic modification that plays a crucial role in the pathological progression of ocular diseases.DNA methylation can regulate gene expression,thereby affecting cell function and signal transduction.Ophthalmic diseases are a kind of complex diseases,and their pathogenesis involves many factors such as genetic,environmental and individual differences.In addition,inflammation,oxidative stress and lipid metabolism,which abnormal DNA methylation is closely related to,are also considered to be major factors in eye diseases.The current understanding of DNA methylation in eye diseases is becoming more complex and comprehensive.In addition to the simple suppression of gene expression by hypermethylation,factors such as hypomethylation or demethylation,DNA methylation in non-promoter regions,interactions with other epigenetic modifications,and dynamic changes in DNA methylation must also be considered.Interestingly,although some genes are at abnormal methylation levels,their expression is not significantly changed,which indirectly reflects the complexity of gene regulation.This review aims to summarize and compare some relevant studies,and provide with new ideas and methods for the prevention and treatment of different eye diseases,such as glaucoma,retinoblastoma,and diabetic retinopathy.
基金supported by the Fundamental Research Funds for the Central Universities(2572020DR10)Project on the Investigation,Supervision and Industry Regulation of Rare and Endangered Species(2024)。
文摘Illegal hunting and trafficking of wildlife and their derivatives extort unprecedented population decline of relatively many species pushing them towards extinction.Notwithstanding contemporary counteracting interventions at international,regional,national and local levels,wildlife farming is advocated as an alternative approach to minimize pressure on wild populations.For wildlife farming to be an effective conservation tool,the integration of wildlife forensics is inevitable to allow distinction between captive-bred and wild-caught species.To this end,we analyzed methylation rates of skeletal muscle samples(pectoralis major,triceps brachii,gastrocnemius,biceps femoris,and neck muscles)from 60 captive-bred and 30 wild-caught Common Pheasant.A total of 13,507 differentially methylated regions were identified between five wild-caught and five captive-bred individuals through whole-genome methylation sequencing(WGBS).Based on the selected five methylation sites,LOC116231076,LOC116242223,ATAD2B,EGFL6,and HS2ST,quantitative detection technique was developed using methylation-sensitive high-resolution melting curve(MS-HRM)to measure methylation rates.The results showed significant differences in methylation rates at all differential sites between wild-caught and captive-bred individuals(|t|=0.67–33.10,P=0.000–0.042).The discrimination accuracy rate of each locus was highest in the gastrocnemius muscle and lowest in the neck muscle.The discrimination accuracy rate on LOC116231076,LOC116242223,ATAD2B,EGFL6,and HS2ST methylation sites for gastrocnemius muscle was 64.98%,100.00%,68.54%,63.79%,and 63.70%,respectively;and for neck muscle it was 67.42%,68.06%,83.61%,65.04%,and68.85%,respectively.The united discrimination accuracy rate of the five loci were 100.00%for gastrocnemius muscle,99.78%for biceps femoris muscle,97.52%for pectoralis major muscle,93.96%for triceps brachii muscle,and 91.63%for neck muscle,respectively.The panel also revealed excellent repeatability,reproducibility,sensitivity and universality to mammals and avian species.This study establishes an effective,accurate and low-cost identification technology for the identification of wild and farmed Common Pheasant,and also provides a reference for the development of identification methods for other species.
基金the Research Program of the Science and Technology Department of Yunnan Province,No.202101AY070001-204.
文摘BACKGROUND Gastric cancer(GC)is a malignant tumor originating from gastric mucosal epithelial cells that has high morbidity and mortality.microRNAs(miR)are important diagnostic markers and therapeutic targets in this disease.AIM To explore the mechanism of miR-125a-5p in the pathogenesis of GC.METHODS The expression levels of miR-125a-5p,SERPINE1 and DNMT1 in GC cells and tissues were detected by real-time polymerase chain reaction(PCR)and Western blotting.Methylation-specific PCR was used to detect the level of miR-125a-5p methylation.A cell counting kit 8 assay,scratch test,and a Transwell assay were performed to detect the proliferation,migration,and invasiveness of HGC27 cells,respectively.The expression of the epithelial mesenchymal transition(EMT)-related proteins E-cadherin,N-cadherin and vimentin in HGC27 cells was detected by Western blotting,while the expression of vimentin was detected by immunofluorescence.RESULTS This study revealed that miR-125a-5p was expressed at low levels in GC clinical samples and cells and that miR-125a-5p overexpression inhibited the proliferation,migration,invasiveness and EMT of GC cells.Mechanistically,miR-125a-5p can reduce GC cell proliferation,promote E-cadherin expression,inhibit N-cadherin and vimentin expression,and reduce the EMT of GC cells,thus constraining GC cells to a certain extent.Moreover,DNMT1 inhibited miR-125a-5p expression by increasing the methylation of the miR-125a-5p promoter,thereby promoting the expression of SERPINE1,which acts together with miR-125a-5p to exert antagonistic effects on GC.CONCLUSION Our study revealed that DNMT1 promoted SERPINE1 protein expression by inducing miR-125a-5p methylation,which led to the proliferation,migration and occurrence of EMT in GC cells.
文摘BACKGROUND Epigenetic regulation of leptin(LEP)plays a critical role in metabolic disorders,yet its promoter methylation patterns in lean diabetic populations remain poorly characterized.Emerging evidence suggests DNA methylation may precede clinical hyperglycemia,offering potential for early risk stratification.While obesity-associated LEP methylation is well-studied,lean Asian populations who exhibit high diabetes prevalence despite lower adiposity,represent an underexplored cohort.This study hypothesizes that LEP promoter methylation in peripheral leukocytes decreases progressively from normoglycemia to prediabetes and type 2 diabetes mellitus(T2DM),correlating inversely with serum LEP levels in lean Chinese adults[body mass index(BMI)<24 kg/m^(2)].AIM To investigate LEP promoter methylation status and its association with serum LEP levels across glycemic states in lean Chinese adults.METHODS We enrolled 392 participants including 120 normoglycemic controls,94 prediabetes[44 impaired fasting glucose(IFG)/50 impaired glucose tolerance(IGT)],178 T2DM aged 40-60 years with BMI<24 kg/m^(2).Genomic DNA from peripheral leukocytes underwent bisulfite conversion followed by methylation-specific PCR to assess CpG methylation in the LEP promoter.Serum LEP was quantified via enzyme-linked immunosorbent assay,with other parameters measured through standard assays.Statistical analyses included analysis of variance,χ²tests,and Pearson correlation(Bonferroni-corrected P value).RESULTS Methylation frequencies declined progressively:59.2%(controls)reduced to 43.6%(prediabetes;IFG:38.6%,IGT:48%)reduced to 31.5%(T2DM)(all P<0.05 vs controls;T2DM vs IGT:P=0.030).Serum LEP levels increased significantly in T2DM(16.94±4.19μg/L)vs controls(11.33±3.10μg/L;P=0.002),with intermediate values in prediabetes(IFG:13.79±3.32μg/L;IGT:12.62±4.81μg/L).A near-perfect inverse correlation between methylation and LEP levels was observed(r=-0.95,95%CI:-0.97 to-0.92,P<0.001),persisting after adjusting for age and BMI(β=-0.91,P<0.001).CONCLUSION LEP promoter hypomethylation parallels worsening glycemic status in lean Chinese adults,suggesting its potential as a blood-based epigenetic biomarker for diabetes progression,pending validation in longitudinal cohorts.
基金supported by the Shanghai 3-year Public Health Action Plan(grant number:GWVI-11.1-39).
文摘Cyclic volatile methyl siloxanes(cVMSs)are widely used in industrial and consumer products because of their thermal stability,low reactivity,and reduced surface tension[1].Their extensive use has resulted in environmental pollution globally.Recognized as very persistent and very bioaccumulative(vPvB),compounds such as octamethylcyclotetrasiloxane(D4),decamethylcyclopentasiloxane(D5),and dodecamethylcyclohexasiloxane(D6)are regulated in the European Union[2]and are monitored worldwide.
基金supported by the National Natural Science Foundation of China(32070607)the National Key Research and Development Program of China(2020YFA0804000)the CAS Project for Young Scientists in Basic Research(YSBR-012).
文摘In the mammalian genome,most CpGs are methylated.However,CpGs within the CpG islands(CGIs)are largely unmethylated,which are important for gene expression regulation.The mechanism underlying the low methylation levels at CGIs remains largely elusive.KDM2 proteins(KDM2A and KDM2B)are H3K36me2 demethylases known to bind specifically at CGIs.Here,we report that depletion of each or both KDM2 proteins,or mutation of all their JmjC domains that harbor the H3K36me2 demethylation activity,leads to an increase in DNA methylation at selective CGIs.The Kdm2a/2b double knockout shows a stronger increase in DNA methylation compared with the single mutant of Kdm2a or Kdm2b,indicating that KDM2A and KDM2B redundantly regulate DNA methylation at CGIs.In addition,the increase of CGI DNA methylation upon mutations of KDM2 proteins is associated with the chromatin environment.Our findings reveal that KDM2A and KDM2B function redundantly in regulating DNA methylation at a subset of CGIs in an H3K36me2 demethylation-dependent manner.
基金National Key Research and Development Program of China,No.2016YFA0100800(to LC)International(Regional)Cooperation and Communication Program of the National Natural Science Foundation of China,No.81820108013(to LC)+3 种基金State Key Program of the National Natural Science Foundation of China,No.81330030(to LC)National Natural Science Foundation of China,Nos.82071370(to ZW),81301042(to LC)Shanghai Pujiang Program,No.19PJ1409200(to ZW)Shanghai Sailing Program,No.21YF1442400(to CL)。
文摘DNA methylation is a critical epigenetic regulator in the occurrence and development of diseases and is closely related to various functional responses in relation to spinal cord injury.To investigate the role of DNA methylation in spinal cord injury,we constructed a library with reduced-representation bisulfite sequencing data obtained at various time points(day 0-42)after spinal cord injury in mice.Global DNA methylation levels,specifically non-CpG(CHG and CHH)methylation levels,decreased modestly following spinal cord injury.Stages post-spinal cord injury were classified as early(day 0-3),intermediate(day7-14),and late(day 28-42)based on similarity and hie rarchical cluste ring of global DNA methylation patterns.The non-CpG methylation level,which included CHG and CHH methylation levels,was markedly reduced despite accounting for a minor proportion of total methylation abundance.At multiple genomic sites,including the 5’untranslated regions,promoter,exon,intron,and 3’untranslated regions,the non-CpG methylation level was markedly decreased following spinal cord injury,whereas the CpG methylation level remained unchanged at these locations.Approximately one-half of the differentially methylated regions were located in intergenic areas;the other differentially methylated regions in both CpG and non-CpG regions were cluste red in intron regions,where the DNA methylation level was highest.The function of genes associated with differentially methylated regions in promoter regions was also investigated.From Gene Ontology analysis results,DNA methylation was implicated in a number of essential functional responses to spinal cord injury,including neuronal synaptic connection creation and axon regeneration.Notably,neither CpG methylation nor non-CpG methylation was implicated in the functional response of glial or inflammatory cells.In summary,our work elucidated the dynamic pattern of DNA methylation in the spinal co rd following injury and identified reduced nonCpG methylation as an epigenetic target after spinal cord injury in mice.
基金funded by National High-Level Hospital Clinical Research Funding (2022-PUMCH-A-203)CAMS Innovation Fund for Medical Sciences (2021-I2M-1-001)+4 种基金Health Research & Special Projects Grant of China (201002020 and 201502005)The Integrated Entrusted Project of Research Funding at Peking Union Medical College Hospital (ZC201903347)the National Natural Science Foundation of China (81970495)Capital Health Development Scientific Research Fund (2022-2-4014)Peking Union Medical College Hospital Research Funding for Postdoc (kyfyjj202315)
文摘Colitis-associated colorectal cancer(CAC),a serious complication of ulcerative colitis(UC),is associated with a poor prognosis.The vitamin D receptor(VDR)is recognized for its protective role in UC and CAC through the maintenance of intestinal barrier integrity and the regulation of inflammation.This study demonstrates a significant reduction in m^(6)A-related genes,particularly methyltransferase like 14(METTL14),in UC and CAC patients and identifies an association between METTL14 and VDR.In the azoxymethane(AOM)/dextran sodium sulfate(DSS)-induced mousemodel,vitamin D treatment increases METTL14 expression and reduces tumorburden,while Vdr-knockout mice exhibit lower METTL14 levels and increased tumorigenesis.In vitro,the VDR agonist calcipotriol upregulates METTL14 in NCM460 cells,with this effect attenuated by VDR knockdown.VDRknockdown inDLD-1colon cancer cellsdecreases METTL14 expressionand promotes proliferation,which is reversed by METTL14 overexpression.Mechanistic studies reveal that VDR regulates METTL14 expression via promoter binding,modulating key target genes such as SOX4,DROSH,and PHLPP2.This study highlights the role of the VDR-METTL14 axis as a protective mechanism in CAC and suggests its potential as a therapeutic target for preventing and treating CAC.
文摘Homoisoflavonoids are in the subclass of the larger family of flavonoids having one more alkyl carbon than flavonoids. Among them, 8-C-Methylated homoisoflavones have not been extensively studied for synthesis and biological evaluation. Author’s current objective is to synthesize 8-C-Methylated homoisoflavones by the reaction of 3-C-methylated dihydrochalcones with N,N’-dimethyl (chloromethylene) ammonium chloride generated in situ from DMF and PCl<sub>5</sub> for one carbon extension at about room temperature. The 3-C-methylated dihydrochalcones were synthesized by the reduction of 3-C-methylated chalcones, which were prepared from 3-C-methylated acetophenones and aromatic aldehydes in the presence of base. All the synthesized novel homoisoflavones’s structures were characterized by NMR and Tandem Mass Spectrometry.
基金supported by the National Natural Science Foundation of China,Nos.82271283(to XC),91854115(to JW),31970044(to JW)the Natural Science Foundation of Beijing,No.7202001(to XC)the Scientific Research Project of Beijing Educational Committee,No.KM202010005022(to XC)。
文摘Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.
基金supported by the grant from the National Natural Science Foundation of China (No. 21210003)
文摘RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species-specific. However, people rarely know their biological functions. There are several identified methylation modifications in eukaryotic messenger RNA （mRNA）, such as NT-methylguanosine （mVG） at the cap, Nr-methyl-2＇-O-methyladenosine （m6Am）, 2＇-O-methylation （Nm） within the cap and the internal positions, and internal N6-methyladenosine （m6A） and 5-methylcytosine （mSC）. Among them, mTG cap was studied more clearly and found to have vital roles in several important mRNA processes like mRNA translation, stability and nuclear export, m6A as the most abundant modification in mRNA was found in the 1970s and has been proposed to function in mRNA splicing, translation, stability, transport and so on. mrA has been discovered as the first RNA reversible modification which is demethylated directly by human fat mass and obesity associated protein （FRO） and its homolog protein, alkylation repair ho- molog 5 （ALKBH5）. b-TO has a special demethylation mechanism that demethylases m6A to A through two over-oxidative intermediate states： N6-hydroxymethyladenosine （hm6A） and Nr-formyladenosine （frA）. The two newly discovered m6A demethylases, bTO and ALKBH5, significantly control energy homeostasis and spermatogenesis, respectively, indicating that the dynamic and reversible mrA, analogous to DNA and histone modifications, plays broad roles in biological kingdoms and brings us an emerging field ＂RNA Epige- netics＂. 5-methylcytosine （5mC） as an epigenetic mark in DNA has been studied widely, but mSC in mRNA is seldom explored. The bisulfide sequencing showed mSC is another abundant modification in mRNA, suggesting that it might be another RNA epigenetic mark. This review focuses on the main methylation modifications in mRNA to describe their formation, distribution, function and demethylation from the current knowledge and to provide future 19erspectives on functional studies.
文摘Pancreatic cancer(PanCa)presents a catastrophic disease with poor overall survival at advanced stages,with immediate requirement of new and effective treatment options.Besides genetic mutations,epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target.Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails.Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients.Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies.Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance.Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions,and novel pharmacological strategies that target these components could potentially lead to breakthroughs.We aim to highlight the possibilities that exist and the potential therapeutic interventions.
基金Supported by the Medical Talents of Wuhan Health and Family Planning Commission,No.2017[51](to Yu J)the Medical Talents of Wuhan Hospital of Traditional Chinese and Western Medicine(to Yu J)+1 种基金the Hubei Natural Science Foundation,No.2023AFB1091Wuhan Medical Research Project,No.WX23A36(to Yu J).
文摘BACKGROUND Cholangiocarcinoma(CCA),also known as bile duct cancer,is a devastating malignancy primarily affecting the biliary tract.AIM To assess their performance in clinical diagnosis and monitoring of CCA,plasma methylation and circulating tumor cells were detected.METHODS Plasma samples were collected from Hubei Cancer Hospital(n=156).Plasma DNA was tested to detect SHOX2,HOXA9,SEPTIN9,and RASSF1A methylation using TaqMan PCR.Circulating tumor cells(CTCs)were detected in the peripheral blood of patients using the United States Food and Drug Administration-approved cell search system before and after clinical therapy.The CCA diagnostic value was estimated using the area under the curve.The independent prognosis risk factors for patients with CCA were estimated using Cox and logistic regression analyses.RESULTS The sensitivity and specificity of the four DNA plasma methylations exhibited 64.74%sensitivity and 93.88%specificity for detecting CCA.The receiver operating characteristic curve of the combined value for CCA diagnosis in plasma was 0.828±0.032.RASSF1A plasma methylation was related to the prognosis of patients with CCA.We determined the prognostic hazard ratio for CCA using CTC count,tumor stage,methylation,and carbohydrate antigen 19-9 levels as key factors.Our overall survival nomogram achieved a C-index of 0.705(0.605-0.805).CONCLUSION SHOX2,HOXA9,SEPTIN9,and RASSF1A plasma methylation demonstrated increased sensitivity for diagnosing CCA.RASSF1A plasma methylation and CTCs were valuable predictors to assess CCA prognosis and recurrence.
基金supported by the Natural Science Foundation of Guangdong Province(Grant Nos.2022A1515111141 and 2023A1515010786)。
文摘DNA methylation plays important roles in regulating gene expression during development.However,little is known about the influence of DNA methylation on secondary metabolism during leaf development in the tea plant(Camellia sinensis).In this study,we combined the methylome,transcriptome,and metabolome to investigate the dynamic changes in DNA methylation and its potential regulatory roles in secondary metabolite biosynthesis.In this study,the level of genomic DNA methylation increased as leaf development progressed from tender to old leaf.It additionally exhibited a similar distribution across the genomic background at the two distinct developmental stages studied.Notably,integrated analysis of transcriptomic and methylomic data showed that DNA hypermethylation primarily occurred in genes of the phenylpropanoid,flavonoid,and terpenoid biosynthesis pathways.The effect of methylation on transcription of these secondary metabolite biosynthesis genes was dependent on the location of methylation(i.e.,in the promoter,gene or intergenic regions)and the sequence context(i.e.,CpG,CHG,or CHH).Changes in the content of catechins and terpenoids were consistent with the changes in gene transcription and the methylation state of structural genes,such as serine carboxypeptidase-like acyltransferases 1A(SCPL1A),leucoanthocyanidin reductase(LAR),and nerolidol synthase(NES).Our study provides valuable information for dissecting the effects of DNA methylation on regulation of genes involved in secondary metabolism during tea leaf development.
基金supported by the Shandong Province Natural Science Foundation of Major Basic Research Program (No.ZR2020ZD34)the Key Projects of the National Natural Science Foundation of China (No.42230706)+3 种基金the National Natural Science Foundation of China (No.42307164)the China Postdoctoral Science Foundation (Nos.2023TQ0191 and 2023M732060)the Shandong Postdoctoral Science Foundation (No.SDBX2023041)and the Qingdao Postdoctoral Science Foundation (No.QDBSH20230202052).
文摘Arsenic(As)methylation in soils affects the environmental behavior of As,excessive accumulation of dimethylarsenate(DMA)in rice plants leads to straighthead disease and a serious drop in crop yield.Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security.Here,soils including unarsenic contaminated(N-As),low-arsenic(L-As),medium-arsenic(M-As),and high-arsenic(H-As)soils were incubated under continuous anoxic,continuous oxic,and consecutive anoxic/oxic treatments respectively,to profile arsenic methylating process and microbial species involved in the As cycle.Under anoxic-oxic(A-O)treatment,methylated arsenic was significantly increased once oxygen was introduced into the incubation system.The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic(A),oxic(O),and oxic-anoxic(O-A)treatments,under which arsenic was methylated slightly and then decreased in all four As concentration soils.In fact,the most plentiful arsenite S-adenosylmethionine methyltransferase genes(arsM)contributed to the increase in As methylation.Proteobacteria(40.8%-62.4%),Firmicutes(3.5%-15.7%),and Desulfobacterota(5.3%-13.3%)were the major microorganisms related to this process.These microbial increasedmarkedly and played more important roles after oxygen was introduced,indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic(flooding)and oxic(drainage)environment.The novel findings provided newinsights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.
基金Supported by National Natural Science Foundation of China,No.82360231Yunnan Basic Research Program General Project,No.202401AT070075+1 种基金Dali Basic Research Program Key Project,No.202301A020021Youth Special Project for Basic Research of Local Universities in Yunnan Province,No.202301BA070001-127.
文摘BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge.Fear conditioning and extinction in animal models offer insights into its mechanisms.Our previous research indi-cates that DNA methyltransferases play a role in fear memory renewal.AIM To investigate the role of DNA methylation in the extinction of fear memory,with the goal of identifying potential strategies to enhance the efficacy of exposure therapy for fear-related disorders.METHODS This study investigated the role of DNA methylation in fear memory extinction in mice.DNA methylation was manipulated using N-phthalyl-L-tryptophan(RG108)to reduce methylation and L-methionine injections to enhance it.Neuronal activity,and dendritic spine density was measured following extinction training.RESULTS RG108 suppressed extinction,reduced spine density,and inhibited neuronal activity.Methionine injections facilitated extinction.CONCLUSION DNA methylation is crucial for fear memory extinction.Enhancing methylation may improve the efficacy of exposure therapy,offering a potential strategy to treat fear-related disorders.
基金supported by the National Natural Science Foundation of China(Nos.82274211 and 82474190)the Natural Science Foundation of Tianjin(Nos.24JCZDJC00120 and 24PTLYHZ00280)Liaoning Provincial Department of Education Basic Research Projects for Higher Education Institutions(No.LJ212510163021)。
文摘Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This study demonstrates that tenacissoside I(TI),a compound isolated from Marsdenia tenacissima(Roxb.)Wight et Arn,traditionally used in clinical practice as an ethnic medicine for cancer treatment,exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells.TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin(DOX)and paclitaxel(PAC)by downregulating ABCB1 expression and reducing ABCB1 drug transport function.Mechanistically,protein arginine methyltransferase 1(PRMT1),whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues,was differentially expressed in TI-treated SW620/AD300 cells.SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine(aDMA)and enhanced PRMT1-EGFR interaction compared to their parental cells.Moreover,TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR,PRMT1-EGFR interaction,and EGFR downstream signaling in SW620/AD300 and KBV200 cells.These effects were significantly reversed by PRMT1 overexpression.Additionally,TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities.This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR,suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.
基金supported by the National Key R&D Program of China(2023YFD1300103)the Science and Technology Plan Project of Yantai City(2023ZDCX024)+5 种基金the National Natural Science Foundation of China(32372852)the Science Fund for Distinguished Young Scholars of Shaanxi Province(2024JC-JCQN-30)Shaanxi Provincial Innovation Leadership Program in Sciences and Technologies for Young and Middle-aged Scientists(2023SR205)the China Agriculture Research System-beef(CARS-37)the Innovation Team of Cattle Industry in Technological System of Shandong Modern Agriculture Industry(SDAIT-09-03)the Key Research and Development Project in Shandong Province(Competitive Innovation Platform)(2022CXPT010).
文摘Background N^(6)-methyladenosine(m^(6)A)methylation is a key epigenetic modification that can modulate gene expression and strongly affect mammalian developmental processes.However,the genome-wide methylation of long non-coding RNAs(lncRNAs)and its implications for the development of skeletal muscle remain poorly understood.Bovine skeletal muscle samples from five developmental stages were analyzed in this study to establish lncRNA methylome and transcriptomic maps.Results Globally,59.67%of lncRNAs in skeletal muscle with m^(6)A modifications,and this percentage decreased progressively during development.lncRNA expression levels were positively associated with the number of m^(6)A peaks,with lncRNAs possessing 3 or more peaks showing significantly higher expression levels than those with 1 or 2 peaks.Specific lncRNAs involved in skeletal muscle development were identified through two analytical approaches.The first approach employed weighted gene co-expression network analysis(WGCNA)of transcriptomic data to identify correlations between annotated lncRNAs and growth-related traits,resulting in 21 candidate hub lncRNAs.The intersection of these 21 hub lncRNAs with 151 differentially methylated lncRNAs(DM-lncRNAs)identified 10 shared candidate lncRNAs.The second approach integrated MeRIP-seq and RNA-seq data to identify 36 lncRNAs that were both differentially m^(6)A modified and differentially expressed(dme-lncRNAs).GO and KEGG enrichment analyses of cis-target genes associated with these dme-lncRNAs identified eight candidate lncRNAs.Combining the results from the two approaches identified 16 key m^(6)A-modified lncRNAs likely involved in skeletal muscle development.Conclusions These findings highlight the regulatory and functional significance of dynamic lncRNA methylation in skeletal muscle development.
