AIM： To evaluate the clinical significance of CpG island methylator phenotype （CIMP） in plasma and its association with hepatocellular carcinoma （HCC） progress. METHODS： CIMP status of 108 HCC patients was analy...AIM： To evaluate the clinical significance of CpG island methylator phenotype （CIMP） in plasma and its association with hepatocellular carcinoma （HCC） progress. METHODS： CIMP status of 108 HCC patients was analyzed using a methylation marker panel in tumor tissues and plasma with methylation-specific polymerase chain reaction. Fifteen samples of non-neoplastic liver tissues and 60 of plasma from healthy persons were examined simultaneously. Examined genes included APC, WIF-1, RUNX-3, DI C-1, SFRP-1, DKK and E-cad.26/108, 24.07% in plasma; WIF-1, 53/108, 49.07% in tissue and 35/108, 32.41% in plasma; RUNX-3, 52/108, 48.14% in tissue and 42/108, 38.89% in plasma; DIC-1, 38/108, 35.18% in tissue and 23/108, 21.30% in plasma; SFRP-1, 40/108, 37.04% in tissue and 31/108, 28.7% in plasma; DKK, 39/108, 36.1% in tis- sue and 25/108, 23.14% in plasma; and E-cad, 37/108, 34.3% in tissue and 18/108, 16.67% in plasma. CIMP＋ （≥3 methylated genes） was detected in 68 （60.2%） tumor tissue samples and 62 （57.4%） plasma samples. CIMP was not detected in non-neoplastic liver tissues or plasma of healthy persons. CIMP status in tumor tissues differed significantly in gender, hepatitis B surface antigen, alpha-fetoprotein, and tumor-node- metastasis stage （P 〈 0.05）. Similar results were obtained with plasma samples （P 〈 0.05）. There was no difference in CIMP status in age, presence of hepatitis C virus antibody, cirrhosis, number of nodes, number of tumors, tumor size, or Edmondson-Steiner stage. A one-year follow-up found that the metastatic rate and recurrence rate in the CIMP＋ group were significantly higher than in the CIMP- group as assessed with plasma samples （P 〈 0.05）. CONCLUSION： Plasma DNA can be a reliable sample source for CIMP analysis. CIMP in plasma may serve as a molecular marker of late-stage and poor-prognosis HCC.展开更多
AIM： To investigate the association between the CpG island methylator phenotype （CIMP） and serum Helico- bacter pylori （H. pylori） levels for clinical prediction of gastric cancer （GC） progression. METHODS： We...AIM： To investigate the association between the CpG island methylator phenotype （CIMP） and serum Helico- bacter pylori （H. pylori） levels for clinical prediction of gastric cancer （GC） progression. METHODS： We analyzed the serum ClMP status of 75 patients with GC using a methylation marker panel and a methylation-specific polymerase chain reaction. Serum samples from 40 healthy persons were examined at the same time. The genes examined were APC, WIF-1, RUNX-3, DLC-1, SFRP-1, DKK and E-cad. H. pylori infec- tion in serum was assayed with an anti-H, pylori immu- noglobulin G antibody test and a rapid urease test. RESULTS： The frequencies of high-level methylation in GC tissues for the seven genes were： 48% for APC, 57.33% for WIF-1, 56% for RUNX-3, 50.67% for DLC-1, 52% for SFRP-1, 54.67% for DKK, and 48% for E-cad.The frequencies in GC serum were 30.67% for APC, 34.67% for WIF-1, 37.33% for RUNX-3, 29.33% for DLC-1, 33.33% for SFRP-1, 32% for DKK, and 26.67% for E-cad. CIMP＋ （defined as ≥ 3 methylated genes） was associated with 47 （62.67%） GC tissue samples and 44 （58.67%） GC serum samples. CIMP＋ was not associated with non-neoplastic mucosal tissues or the serum of healthy persons. Of the 75 GC cases, 51 （68%） were H. pylori＋, and 24 （32%） were H. pylori-. Of the 51 H. pylori＋ cases, 36 were CIMP＋ and 15 were CIMP-. In contrast, for the 24 H. pylori- cases, 11 were CIMP＋, and 13 were CIMP-. The difference was signifi- cant between the H. pylori＋ and H. pylori- groups χ2 = 4.27, P 〈 0.05）. Of the 51 H. pylori＋ GC patients, 34 were CIMP＋ and 17 were CIMP-, while among the 24 H. pylori- GC cases, 10 were CIMP＋ and 14 were CIMP-. The difference was significant between the H. pylori＋ and H. pylori- groups （χ2 = 4.21, P 〈 0.05）. A 2-year follow-up showed significant difference in the rates of metastasis and recurrence between H. pylori＋/CIMP＋ cases and the H. pylori＋/CIMP- cases or CIMP- cases associated with H. pylori assayed in serum （P 〈 0.05）. However, there were no significant differences in sur- vival rates between the two groups. CONCLUSION： H. pylori＋/CIMP＋ cases are associ- ated with higher rates of metastasis and recurrence thanH, pylori＋/CIMP- cases. Serum may be useful for examining CIMP status.展开更多
Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational res...Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype(CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using crossplatform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600 E mutation, CDKN2 A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.展开更多
To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODSPatients undergoing NACRT and surgical resection for ...To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODSPatients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed. RESULTSThere were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced “T” stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence. CONCLUSIONWe report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.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
Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytoki...Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.展开更多
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
Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells...Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.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
During the hyperacute phase of intracerebral hemorrhage(ICH),the mass effect and blood components mechanically lead to brain damage and neurotoxicity.Our findings revealed that the mass effect and transferrin precipit...During the hyperacute phase of intracerebral hemorrhage(ICH),the mass effect and blood components mechanically lead to brain damage and neurotoxicity.Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake,culminating in ferroptosis in neurons.M6A(N6-methyladenosine)modification,the most prevalent mRNA modification,plays a critical role in various cell death pathways.The Fto(fat mass and obesity-associated protein)demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels.Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis.Applying nanopore direct RNA sequencing,we identified voltage-dependent anion channel 3(Vdac3)as a potential target associated with ferroptosis.Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA.These findings elucidate the intricate interplay between Fto,Vdac3,m6A methylation,and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.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
Aegilops speltoides,the closest ancestor of the wheat B subgenome,has been well studied genomically.However,the epigenetic landscape of Ae.speltoides and the effects of epigenetics on its growth and development remain...Aegilops speltoides,the closest ancestor of the wheat B subgenome,has been well studied genomically.However,the epigenetic landscape of Ae.speltoides and the effects of epigenetics on its growth and development remain poorly understood.Here,we present a comprehensive multi-omics atlas of leaves and roots in Ae.speltoides,encompassing transcriptome,DNA methylation,histone modifications,and small RNA profiling.Divergent DNA methylation levels were detected between leaves and roots,and were associated with differences in accumulated 24-nt siRNAs.DNA methylation changes in promoters and gene bodies showed strong connections with altered expression between leaves and roots.Transcriptional regulatory networks(TRN)reconstructed between leaves and roots were driven by tissue-specific TF families.DNA methylation and histone modification act together as switches that shape root and leaf morphogenesis by modulating the binding of tissue-specific TFs to their target genes.The TRNs in leaves and roots reshaped during wheat polyploidization were associated with alterations in epigenetic modi-fications.Collectively,these results not only shed light on the critical contribution of epigenetic regulation in the morphogenesis of leaves and roots in Ae.speltoides but also provide new insights for future investigations into the complex interplay of genetic and epigenetic factors in the developmental biology of common wheat.展开更多
Juglans sigillata is an economically valuable nut crop renowned for its nutritional richness,including essential nutrients,antioxidants,and healthy fats,which boost human cardial,brain and gut health.Despite its impor...Juglans sigillata is an economically valuable nut crop renowned for its nutritional richness,including essential nutrients,antioxidants,and healthy fats,which boost human cardial,brain and gut health.Despite its importance,the lack of a complete genome assembly has been a stumbling block in its biological breeding process.Therefore,we generated deep coverage ultralong Oxford Nanopore Technology(ONT)and PacBio HiFi reads to construct a telomere-to-telomere(T2T)genome assembly.The final assembly spans 537.27 Mb with no gaps,demonstrating a remarkable completeness of 98.1%.We utilized a combination of transcriptome data and homologous proteins to annotate the genome,identifying 36018 protein-coding genes.Furthermore,we profiled global cytosine DNA methylations using ONT sequencing data.Global methylome analysis revealed high methylation levels in transposable element(TE)-rich chromosomal regions juxtaposed with comparatively lower methylation in gene-rich areas.By integrating a detailed multi-omics data analysis,we obtained valuable insights into the mechanism underlying endopleura coloration.This investigation led to the identification of eight candidate genes(e.g.ANR)involved in anthocyanin biosynthesis pathways,which are crucial for the development of color in plants.The comprehensive genome assembly and the understanding of the genetic basis of important traits like endopleura coloration will open avenues for more efficient breeding programs and improved crop quality.展开更多
N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis a...N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m^(6)A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m^(6)A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m^(6)A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m^(6)A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m^(6)A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m^(6)A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m^(6)A's role in neurodegenerative processes. The roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.展开更多
Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulat...Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulating various amyloid-βoligomers in the brain,influenced by complex genetic and environmental factors.The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer’s disease are believed to primarily result from synaptic dysfunction.Throughout life,environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders.These changes,known as epigenetic modifications,also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity.In this context,we highlight recent advances in understanding the roles played by key components of the epigenetic machinery,specifically DNA methylation,histone modification,and microRNAs,in the development of Alzheimer’s disease,synaptic function,and activity-dependent synaptic plasticity.Moreover,we explore various strategies,including enriched environments,exposure to non-invasive brain stimulation,and the use of pharmacological agents,aimed at improving synaptic function and enhancing long-term potentiation,a process integral to epigenetic mechanisms.Lastly,we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer’s disease.We suggest that addressing Alzheimer’s disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.展开更多
As the most prevalent post-transcriptional modification in transfer RNAs(tRNAs),methylation dynamically and reversibly regulates the biosynthesis and maturation of tRNAs,exerting direct impacts on the abundance and fu...As the most prevalent post-transcriptional modification in transfer RNAs(tRNAs),methylation dynamically and reversibly regulates the biosynthesis and maturation of tRNAs,exerting direct impacts on the abundance and functions of tRNAs responsible for the accurate translation of messenger RNAs(mRNAs).Consequently,aberrant tRNA methylation can potentially lead to the production of abnormally expressed proteins and the dysregulation of cellular homeostasis,underscoring the significance of tRNA methylation in tumorigenesis.Recent research has highlighted the aberrant expression of its catalytic regulators and proposed mechanisms through which tRNA methylation directly or indirectly influences tumor biological characteristics.This review provides a comprehensive summary of current research on tRNA methylation and its role in cellular function,aiming to deepen our understanding of the biological significance of tRNA methylation in tumorigenesis and to explore the potential of targeting tRNA methylation and tRNA-derived small RNAs(tsRNAs)for cancer therapy.展开更多
Epigenetic regulation in the rumen,a unique ruminant organ,remains largely unexplored compared with other tissues studied in model species.In this study,we perform an in-depth analysis of the epigenetic and transcript...Epigenetic regulation in the rumen,a unique ruminant organ,remains largely unexplored compared with other tissues studied in model species.In this study,we perform an in-depth analysis of the epigenetic and transcriptional landscapes across fetal and adult bovine tissues as well as pluripotent stem cells.Among the extensive methylation differences across various stages and tissues,we identify tissue-specific differentially methylated regions(tsDMRs)unique to the rumen,which are crucial for regulating epithelial development and energy metabolism.These tsDMRs cluster within super-enhancer regions that overlap with transcription factor(TF)binding sites.Regression models indicate that DNA methylation,along with H3K27me3 and H3K27ac,can be used to predict enhancer activity.Key upstream TFs,including SOX2,FOSL1/2,and SMAD2/3,primarily maintain an inhibitory state through bivalent modifications during fetal development.Downstream functional genes are maintained mainly in a stable repressive state via DNA methylation until differentiation is complete.Our study underscores the critical role of tsDMRs in regulating distal components of rumen morphology and function,providing key insights into the epigenetic regulatory mechanisms that may influence bovine production traits.展开更多
基金Supported by The Department of Health of Jiangsu Province,China,No.H200957
文摘AIM： To evaluate the clinical significance of CpG island methylator phenotype （CIMP） in plasma and its association with hepatocellular carcinoma （HCC） progress. METHODS： CIMP status of 108 HCC patients was analyzed using a methylation marker panel in tumor tissues and plasma with methylation-specific polymerase chain reaction. Fifteen samples of non-neoplastic liver tissues and 60 of plasma from healthy persons were examined simultaneously. Examined genes included APC, WIF-1, RUNX-3, DI C-1, SFRP-1, DKK and E-cad.26/108, 24.07% in plasma; WIF-1, 53/108, 49.07% in tissue and 35/108, 32.41% in plasma; RUNX-3, 52/108, 48.14% in tissue and 42/108, 38.89% in plasma; DIC-1, 38/108, 35.18% in tissue and 23/108, 21.30% in plasma; SFRP-1, 40/108, 37.04% in tissue and 31/108, 28.7% in plasma; DKK, 39/108, 36.1% in tis- sue and 25/108, 23.14% in plasma; and E-cad, 37/108, 34.3% in tissue and 18/108, 16.67% in plasma. CIMP＋ （≥3 methylated genes） was detected in 68 （60.2%） tumor tissue samples and 62 （57.4%） plasma samples. CIMP was not detected in non-neoplastic liver tissues or plasma of healthy persons. CIMP status in tumor tissues differed significantly in gender, hepatitis B surface antigen, alpha-fetoprotein, and tumor-node- metastasis stage （P 〈 0.05）. Similar results were obtained with plasma samples （P 〈 0.05）. There was no difference in CIMP status in age, presence of hepatitis C virus antibody, cirrhosis, number of nodes, number of tumors, tumor size, or Edmondson-Steiner stage. A one-year follow-up found that the metastatic rate and recurrence rate in the CIMP＋ group were significantly higher than in the CIMP- group as assessed with plasma samples （P 〈 0.05）. CONCLUSION： Plasma DNA can be a reliable sample source for CIMP analysis. CIMP in plasma may serve as a molecular marker of late-stage and poor-prognosis HCC.
基金Supported by Department of Health of Jiangsu Province o China,No.H200957
文摘AIM： To investigate the association between the CpG island methylator phenotype （CIMP） and serum Helico- bacter pylori （H. pylori） levels for clinical prediction of gastric cancer （GC） progression. METHODS： We analyzed the serum ClMP status of 75 patients with GC using a methylation marker panel and a methylation-specific polymerase chain reaction. Serum samples from 40 healthy persons were examined at the same time. The genes examined were APC, WIF-1, RUNX-3, DLC-1, SFRP-1, DKK and E-cad. H. pylori infec- tion in serum was assayed with an anti-H, pylori immu- noglobulin G antibody test and a rapid urease test. RESULTS： The frequencies of high-level methylation in GC tissues for the seven genes were： 48% for APC, 57.33% for WIF-1, 56% for RUNX-3, 50.67% for DLC-1, 52% for SFRP-1, 54.67% for DKK, and 48% for E-cad.The frequencies in GC serum were 30.67% for APC, 34.67% for WIF-1, 37.33% for RUNX-3, 29.33% for DLC-1, 33.33% for SFRP-1, 32% for DKK, and 26.67% for E-cad. CIMP＋ （defined as ≥ 3 methylated genes） was associated with 47 （62.67%） GC tissue samples and 44 （58.67%） GC serum samples. CIMP＋ was not associated with non-neoplastic mucosal tissues or the serum of healthy persons. Of the 75 GC cases, 51 （68%） were H. pylori＋, and 24 （32%） were H. pylori-. Of the 51 H. pylori＋ cases, 36 were CIMP＋ and 15 were CIMP-. In contrast, for the 24 H. pylori- cases, 11 were CIMP＋, and 13 were CIMP-. The difference was signifi- cant between the H. pylori＋ and H. pylori- groups χ2 = 4.27, P 〈 0.05）. Of the 51 H. pylori＋ GC patients, 34 were CIMP＋ and 17 were CIMP-, while among the 24 H. pylori- GC cases, 10 were CIMP＋ and 14 were CIMP-. The difference was significant between the H. pylori＋ and H. pylori- groups （χ2 = 4.21, P 〈 0.05）. A 2-year follow-up showed significant difference in the rates of metastasis and recurrence between H. pylori＋/CIMP＋ cases and the H. pylori＋/CIMP- cases or CIMP- cases associated with H. pylori assayed in serum （P 〈 0.05）. However, there were no significant differences in sur- vival rates between the two groups. CONCLUSION： H. pylori＋/CIMP＋ cases are associ- ated with higher rates of metastasis and recurrence thanH, pylori＋/CIMP- cases. Serum may be useful for examining CIMP status.
基金funded by the Intramural program of the National Human Genome Research Institute,the National Institutes of Health
文摘Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype(CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using crossplatform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600 E mutation, CDKN2 A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.
文摘To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODSPatients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed. RESULTSThere were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced “T” stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence. CONCLUSIONWe report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.
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 National Natural Science Foundation of China,Nos.32070735(to QL),82371321(to QL),82171270(to ZL)Public Service Platform for Artificial Intelligence Screening and Auxiliary Diagnosis for the Medical and Health Industry,Ministry of Industry and Information Technology of the People's Republic of China,No.2020-0103-3-1(to ZL)+2 种基金the Natural Science Foundation of Beijing,No.Z200016(to ZL)Beijing Talents Project,No.2018000021223ZK03(to ZL)Beijing Municipal Committee of Science and Technology,No.Z201100005620010(to ZL)。
文摘Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.
基金Supported by the 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 grants from the National Key R&D Program of China(2022YFC2403000 and 2021YFC2400500)the National Natural Science Foundation of China(32200728 and 32170925)+3 种基金the Clinical Research Project of Shenzhen Medical Academy of Research and Translation(C2301008)Shenzhen Science and Technology Program(JCYJ20220531100406014,JCYJ2022081800807016,RCBS20221008093336088,KQTD20210811090115019)Guangdong Basic and Applied Basic Research Foundation(2021A1515110375)the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210601).
文摘Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.
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 Key R&D Program of China(2022YFE0131000)the National Natural Science Foundation of China(82220108012,82271306,and 82071307)+1 种基金The Science and Education for Health Foundation of Suzhou for Youth(KJXW2023001)the Boxi Youth Natural Science Foundation(BXQN2023028).
文摘During the hyperacute phase of intracerebral hemorrhage(ICH),the mass effect and blood components mechanically lead to brain damage and neurotoxicity.Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake,culminating in ferroptosis in neurons.M6A(N6-methyladenosine)modification,the most prevalent mRNA modification,plays a critical role in various cell death pathways.The Fto(fat mass and obesity-associated protein)demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels.Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis.Applying nanopore direct RNA sequencing,we identified voltage-dependent anion channel 3(Vdac3)as a potential target associated with ferroptosis.Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA.These findings elucidate the intricate interplay between Fto,Vdac3,m6A methylation,and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.
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.
基金supported by the National Key Research and Development Program of China(2023YFD1200403).
文摘Aegilops speltoides,the closest ancestor of the wheat B subgenome,has been well studied genomically.However,the epigenetic landscape of Ae.speltoides and the effects of epigenetics on its growth and development remain poorly understood.Here,we present a comprehensive multi-omics atlas of leaves and roots in Ae.speltoides,encompassing transcriptome,DNA methylation,histone modifications,and small RNA profiling.Divergent DNA methylation levels were detected between leaves and roots,and were associated with differences in accumulated 24-nt siRNAs.DNA methylation changes in promoters and gene bodies showed strong connections with altered expression between leaves and roots.Transcriptional regulatory networks(TRN)reconstructed between leaves and roots were driven by tissue-specific TF families.DNA methylation and histone modification act together as switches that shape root and leaf morphogenesis by modulating the binding of tissue-specific TFs to their target genes.The TRNs in leaves and roots reshaped during wheat polyploidization were associated with alterations in epigenetic modi-fications.Collectively,these results not only shed light on the critical contribution of epigenetic regulation in the morphogenesis of leaves and roots in Ae.speltoides but also provide new insights for future investigations into the complex interplay of genetic and epigenetic factors in the developmental biology of common wheat.
基金supported by the Yunnan Seed Laboratory,China(202205AR070001-15)the National Natural Science Foundation of China,China(Grant No.32160697)。
文摘Juglans sigillata is an economically valuable nut crop renowned for its nutritional richness,including essential nutrients,antioxidants,and healthy fats,which boost human cardial,brain and gut health.Despite its importance,the lack of a complete genome assembly has been a stumbling block in its biological breeding process.Therefore,we generated deep coverage ultralong Oxford Nanopore Technology(ONT)and PacBio HiFi reads to construct a telomere-to-telomere(T2T)genome assembly.The final assembly spans 537.27 Mb with no gaps,demonstrating a remarkable completeness of 98.1%.We utilized a combination of transcriptome data and homologous proteins to annotate the genome,identifying 36018 protein-coding genes.Furthermore,we profiled global cytosine DNA methylations using ONT sequencing data.Global methylome analysis revealed high methylation levels in transposable element(TE)-rich chromosomal regions juxtaposed with comparatively lower methylation in gene-rich areas.By integrating a detailed multi-omics data analysis,we obtained valuable insights into the mechanism underlying endopleura coloration.This investigation led to the identification of eight candidate genes(e.g.ANR)involved in anthocyanin biosynthesis pathways,which are crucial for the development of color in plants.The comprehensive genome assembly and the understanding of the genetic basis of important traits like endopleura coloration will open avenues for more efficient breeding programs and improved crop quality.
基金supported by the Natural Science Foundation of Heilongjiang Province of China,Outstanding Youth Foundation,No.YQ2022H003 (to DW)。
文摘N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m^(6)A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m^(6)A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m^(6)A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m^(6)A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m^(6)A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m^(6)A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m^(6)A's role in neurodegenerative processes. The roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.
基金supported by a grant from the Massachusetts Alzheimer’s Disease Research Center(5P50 AG 005134)(to SL).
文摘Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulating various amyloid-βoligomers in the brain,influenced by complex genetic and environmental factors.The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer’s disease are believed to primarily result from synaptic dysfunction.Throughout life,environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders.These changes,known as epigenetic modifications,also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity.In this context,we highlight recent advances in understanding the roles played by key components of the epigenetic machinery,specifically DNA methylation,histone modification,and microRNAs,in the development of Alzheimer’s disease,synaptic function,and activity-dependent synaptic plasticity.Moreover,we explore various strategies,including enriched environments,exposure to non-invasive brain stimulation,and the use of pharmacological agents,aimed at improving synaptic function and enhancing long-term potentiation,a process integral to epigenetic mechanisms.Lastly,we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer’s disease.We suggest that addressing Alzheimer’s disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.
基金supported by grants from the National Natural Science Foundation of China(82273174 and 82072374)the Key Research and Development Program of Hunan Province(2023DK2001,2023SK2004,and 2023ZK1122).
文摘As the most prevalent post-transcriptional modification in transfer RNAs(tRNAs),methylation dynamically and reversibly regulates the biosynthesis and maturation of tRNAs,exerting direct impacts on the abundance and functions of tRNAs responsible for the accurate translation of messenger RNAs(mRNAs).Consequently,aberrant tRNA methylation can potentially lead to the production of abnormally expressed proteins and the dysregulation of cellular homeostasis,underscoring the significance of tRNA methylation in tumorigenesis.Recent research has highlighted the aberrant expression of its catalytic regulators and proposed mechanisms through which tRNA methylation directly or indirectly influences tumor biological characteristics.This review provides a comprehensive summary of current research on tRNA methylation and its role in cellular function,aiming to deepen our understanding of the biological significance of tRNA methylation in tumorigenesis and to explore the potential of targeting tRNA methylation and tRNA-derived small RNAs(tsRNAs)for cancer therapy.
基金funded by the Science and Technology Major Project of the Inner Mongolia Autonomous Region of China to the State Key Laboratory of Reproductive Regulation(2023KYPT0010 and 2021ZD0048)STI 2030-Major Projects(2023ZD0407504)of China+1 种基金the development plan for young scientific and technological talents in colleges and universities of Inner Mongolia Autonomous Region of China(NMGIRT2204)the National Natural Science Foundation of China(32160172).
文摘Epigenetic regulation in the rumen,a unique ruminant organ,remains largely unexplored compared with other tissues studied in model species.In this study,we perform an in-depth analysis of the epigenetic and transcriptional landscapes across fetal and adult bovine tissues as well as pluripotent stem cells.Among the extensive methylation differences across various stages and tissues,we identify tissue-specific differentially methylated regions(tsDMRs)unique to the rumen,which are crucial for regulating epithelial development and energy metabolism.These tsDMRs cluster within super-enhancer regions that overlap with transcription factor(TF)binding sites.Regression models indicate that DNA methylation,along with H3K27me3 and H3K27ac,can be used to predict enhancer activity.Key upstream TFs,including SOX2,FOSL1/2,and SMAD2/3,primarily maintain an inhibitory state through bivalent modifications during fetal development.Downstream functional genes are maintained mainly in a stable repressive state via DNA methylation until differentiation is complete.Our study underscores the critical role of tsDMRs in regulating distal components of rumen morphology and function,providing key insights into the epigenetic regulatory mechanisms that may influence bovine production traits.
