The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiqui...The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.展开更多
Hearing loss,which currently affects more than 430 million individuals globally and is projected to exceed 700 million by 2050,predominantly manifests as sensorineural hearing loss(SNHL),for which existing technologie...Hearing loss,which currently affects more than 430 million individuals globally and is projected to exceed 700 million by 2050,predominantly manifests as sensorineural hearing loss(SNHL),for which existing technologies such as hearing aids and cochlear implants fail to restore natural auditory function.Research focusing on protecting inner ear hair cells(HCs)from harmful factors through the regulation of epigenetic modifications has gained significant attention in otology for its role in regulating gene expression without altering the DNA sequence,suggesting potential strategies for preventing and treating SNHL.By synthesizing relevant studies on the inner ear,this review summarizes the emerging roles of histone modifications,DNA methylation,and noncoding RNAs in HC damage,with a focus on their therapeutic potential through epigenetic modulation.Moreover,this review examines the therapeutic potential of epigenetic regulation for the prevention and treatment of SNHL,emphasizing the application of small-molecule epigenetic compounds and their efficacy in modulating gene expression to preserve and restore auditory function.展开更多
Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications wit...Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.展开更多
Radiation-induced lung injury(RILI)is a common complication of radiotherapy.Although berberine(BBR)has been suggested to be associated with reduced RILI incidence,the underlying mechanisms remain unknown.Here,we inves...Radiation-induced lung injury(RILI)is a common complication of radiotherapy.Although berberine(BBR)has been suggested to be associated with reduced RILI incidence,the underlying mechanisms remain unknown.Here,we investigated whether the gut microbiota mediates the radioprotective effects of BBR using a C57BL/6 RILI mouse model with 20 Gy thoracic irradiation(n=6 per group).BBR(100 mg/kg)and inosine(INO,300 mg/kg)were administered orally in vivo.Antibiotic depletion and fecal microbiota transplantation were performed to assess microbiota dependence.Lung injury was assessed by histology,pulmonary function,and cytokine levels.Gut microbiota was analyzed by 16S rRNA sequencing,and metabolites were profiled using LC-MS/MS.Transcriptomic and epigenomic alterations were assessed by RNA sequencing,ATAC sequencing,and CUT&Tag analysis.Molecular docking and surface plasmon resonance were used to assess metabolite-protein interactions.We demonstrated that BBR alleviated RILI in a microbiota-dependent manner.BBR increased Akkermansia muciniphila abundance and metabolite INO levels.Mechanistically,INO was associated with reduced neuron navigator 3(NAV3)expression,accompanied by decreased chromatin accessibility and increased histone H3 lysine 27 trimethylation(H3K27me3)at the NAV3 locus.Together,these findings reveal a gut microbiota-mediated mechanism underlying BBR-mediated protection against RILI,and suggest microbiota-informed biomarkers for risk stratification.展开更多
Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at ma...Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at many levels including nutrient intake,absorption,utilization,and excretion,and can lead to many nutritional disturbances and deficiencies.Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease(ALD).There is growing interest regarding epigenetic changes,including histone modifications that regulate gene expression during disease pathogenesis.Notably,modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation,and control gene transcription.This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD.The review is focused on four critical metabolites,namely,acetate,S-adenosylmethionine,nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD.展开更多
BACKGROUND Pancreatic cancer(PC)is one of the deadliest malignancies with an alarming mortality rate.Despite significant advancement in diagnostics and therapeutics,early diagnosis remains elusive causing poor prognos...BACKGROUND Pancreatic cancer(PC)is one of the deadliest malignancies with an alarming mortality rate.Despite significant advancement in diagnostics and therapeutics,early diagnosis remains elusive causing poor prognosis,marred by mutations and epigenetic modifications in key genes which contribute to disease progression.AIM To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley.METHODS A total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9(CA 19-9),tissue polypeptide specific antigen(TPS),carcinoembryonic antigen(CEA),vascular endothelial growth factor-A(VEGF-A),and epidermal growth factor receptor(EGFR).Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma(KRAS),Breast cancer type 2(BRCA-2),and deleted in pancreatic cancer-4(DPC-4)genes.However,epigenetic modifications(methylation of CpG islands)were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A(p16;CDKN2A),MutL homolog 1(hMLH1),and Ras association domain-containing protein 1(RASSF1A)genes.RESULTS We found significantly elevated levels of biological markers CA 19-9(P≤0.05),TPS(P≤0.05),CEA(P≤0.001),and VEGF(P≤0.001).Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12(16 subjects,P≤0.05),and 13(12 subjects,P≤0.05).However,we did not find a mutation in DPC-4(1203G>T)and BRCA-2(617delT)genes.Furthermore,epigenetic modification revealed that CpG methylation in 21(P≤0.05)and 4 subjects in the promoter regions of the p16 and hMLH1 gene,respectively.CONCLUSION In conclusion,CA 19-9,TPS,CEA,and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC.Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC.Additionally,methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.展开更多
Background:Retinal pigment epithelium(RPE)is vital for the homeostasis of the subretina including photoreceptors and choroid.Interestingly,our previous results suggested that the recently discovered lactate receptor G...Background:Retinal pigment epithelium(RPE)is vital for the homeostasis of the subretina including photoreceptors and choroid.Interestingly,our previous results suggested that the recently discovered lactate receptor GPR81 is abundantly expressed in RPE.To date,only one previous study has shown that activating GPR81 could enhance DNA repair by activating HDAC1.Consequently,we investigated whether GPR81 exhibits epigenetic modification in the subretina by using GPR81−/−mice.Methods:GPR81−/−mice and wide type littermates were generated on a background of C57BL/6J mice.The thicknesses of their choroid were evaluated by immunohistochemistry.Meanwhile,Q-PCR,western blot and choroid sprout assay were performed.In vitro,primary retinal pigment epithelium(pRPE)cells were isolated from mice,and cultured for treatments.Results:The thickness of choroid was reduced in GPR81−/−mice compared to GPR81+/+mice,suggesting that GPR81 is important for the integrity of choroid.In the choroid sprout assay,lactate treated RPE/choroid complex showed a significant increase in angiogenesis compared to controls while lactate treated KO RPE/choroid complex showed no difference compared to their controls.For Q-PCR,most of the genes screened elevated their expression in GPR81−/−mice compared to WT mice,suggesting epigenetic modification may exist,which were confirmed by histone acetylation and HDACs activity assay.Conclusions:Taking together,the lactate receptor GPR81 in RPE is very important for maintaining homeostasis of the subretina.This novel discovery sheds new light on the relationship between metabolism and epigenetic modification.展开更多
Epigenetic modifications modulate conformational structure of chromatin and consequently gene expression by enzyme-mediated chemical modifications of DNA and histones.The activities of epigenetic modifying enzymes dep...Epigenetic modifications modulate conformational structure of chromatin and consequently gene expression by enzyme-mediated chemical modifications of DNA and histones.The activities of epigenetic modifying enzymes depend on many co-substrates and cofactors,such as 2-oxoglutarate(2-OG),iron,S-adenosylmethionine(SAM),nicotinamide adenine dinucleotide(NAD+),flavin adenine dinucleotide(FAD),and acetyl-CoA.These factors are inter-connecting molecules that integrate cellular nutrient metabolism and redox homeostasis,two key regulators of cell proliferation,cell survival,and cell functions.Dysregulation of such delicate regulatory network has been implicated in many pathological conditions and also been increasingly recognized as an emerging mechanism responsible for environmental pollutant-induced adverse effects.In this review,we first summarize DNA and histone modifying enzymes and their essential factors,then discuss the metabolic sources and the redox regulatory roles of these enzymatic factors,and finally elaborate the mechanisms of how targeting such factors by environmental pollutants influences epigenetic regulation and perturbs cellular functions.展开更多
Objective To investigate the treatment effect of the histone demethylase inhibitor GSK-J4,a small molecule that inhibits the demethylase activity of Jumonji domain-containing protein 3(JMJD3),in the treatment of perio...Objective To investigate the treatment effect of the histone demethylase inhibitor GSK-J4,a small molecule that inhibits the demethylase activity of Jumonji domain-containing protein 3(JMJD3),in the treatment of periodontitis.Methods Gingival tissues from patients with moderate to severe chronic periodontitis and healthy controls were collected to evaluate JMJD3 expression via real-time quantitative reverse transcription PCR(RT-qPCR)and immunohistochemistry(IHC).Next,Sprague–Dawley(SD)rats were used to investigate the effect of GSK-J4 in vivo.The experimental periodontitis model was induced by upper first molar ligation and gingival sulcus injection of Porphyromonas gingivalis.The rats were divided into a healthy group,a periodontitis group,periodontitis plus GSK-J4 treatment groups(P+GSK-J415 mg/kg or 25 mg/kg),and a periodontitis plus dimethyl sulfoxide(DMSO)group(P+DMSO).After 4 weeks,maxillary molar segments were assessed via micro-computed tomography(CT)and hematoxylin and eosin(HE)staining.Serum tumor necrosis factor-α(TNF-α)levels were measured by enzyme-linked immunosorbent assay(ELISA).Results Higher expression of the Jmjd3 gene and JMJD3 protein was detected in human inflamed gingiva than in healthy gingiva(P<0.05).GSK-J4 administration reversed alveolar bone absorption[i.e.,reduced alveolar bone crest(ABC)-cementoenamel junction(CEJ)distance],reduced inflammatory cell accumulation at the crest of the alveolar bone,and alleviated serum TNF-αlevels in rats with periodontitis.Moreover,the number of H3K27me3-positive nuclei was greater in model rats treated with GSK J4 than in model rats.Conclusions The histone demethylase inhibitor GSK-J4 attenuated periodontal bone loss and inflammation in a rat periodontitis model by targeting JMJD3.展开更多
MicroRNAs are evolutionarily conserved small noncoding RNA molecules encoded by eukaryotic genomic DNA,and function in post-transcriptional regulation of gene expression via base-pairing with complementary sequences i...MicroRNAs are evolutionarily conserved small noncoding RNA molecules encoded by eukaryotic genomic DNA,and function in post-transcriptional regulation of gene expression via base-pairing with complementary sequences in target mRNAs,resulting in translational repression or degradation of target mRNAs.They represent one of the major types of epigenetic modification and play important roles in all aspects of cellular activities.Altered expression of microRNAs has been found in various human diseases including cancer.Many efforts have been made to discover the characteristic microRNA expression profiles,to understand the roles of aberrantly expressed microRNAs and underlying mechanisms in different cancers.With the application of DNA microarray,real-time quantitative polymerase chain reaction and other molecular biology techniques,increasing evidence has been accumulated which reveal that aberrant microRNAs can be detected not only intracellularly within the cancer cells,but also extracellularly in plasma of patients,postulating the potential of aberrant microRNAs as promising diagnostic/prognostic markers and attracting therapeutic targets.This review is intended to provide the most recent advances in microRNA studies in one of the most common cancers,colorectal cancer,especially the identification of those specifically altered microRNAs in colorectal cancer,validation for their relevance to clinical pathological parameters of patients,functional analyses and potential applications of these microRNAs.展开更多
Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediate...Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediated epigenetic processes in the development of cardio-cerebrovascular injury. HDACs are a family of enzymes to balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. To date, 18 mammalian HDACs are identified and grouped into four classes based on similarity to yeast orthologs. The zinc-dependent HDAC family currently consists of 11 members divided into three classes （class I, II, and IV） on the basis of structure, sequence homology, and domain organization. In comparison, class III HDACs （also known as the sirtuins） are composed of a family of NAD＋-dependent protein-modifying enzymes related to the Sir2 gene. HDAC inhibitors are a group of compounds that block HDAC activities typically by binding to the zinc-containing catalytic domain of HDACs and have displayed an- ti-inflammatory and antifibrotic effects in the cardio-cerebrovascular system. In this review, we summarize the current knowledge about classifications, functions of HDACs and their roles and regulatory mechanisms in the cardio-cerebrovascular system. Pharmacological tar- geting of HDAC-mediated epigenetic processes may open new therapeutic avenues for the treatment of CCVD.展开更多
The sea cucumber, Apostichopusjaponicus, undergoes aestivation to improve survival during periods of high-temperature. During aestivation, the metabolic rate is depressed to reduce the consumption of reserved energy. ...The sea cucumber, Apostichopusjaponicus, undergoes aestivation to improve survival during periods of high-temperature. During aestivation, the metabolic rate is depressed to reduce the consumption of reserved energy. We evaluated the role of epigenetic modification on global gene silencing during metabolic rate depression in the sea cucumber. We compared the expression of epigenetic modifiers in active and aestivating sea cucumbers. The expression of three genes involved in DNA methylation and chromatin remodeling （DNA （cytosine-5）-methyltransferase l, Methyl-CpG-binding domain protein 2）, and Chromodomain-helicase-DNA-binding protein 5） was significantly higher during aestivation （Days 20 and 40）. Similarly, we observed an increase in the expression of genes involved in histone acetylation （Histone deacetylase 3） and Histone-binding protein RBBP4） during the early （Days 5 and 10） and late phases （Days 20 and 40） of aestivation. There was no change in the expression of KAT2B, a histone acetyltransferase. However, the expression of histone methylation associated modifiers （Histone-arginine methyltransferase CARMER and Histone-lysine N-methyltransferase MLL5） was significantly higher after 5 d in the aestivating group. The results suggest that the expression of epigenetic modifiers involved in DNA methylation, chromatin remodeling, histone acetylation, and histone methylation is upregulated during aestivation. We hypothesize that these changes regulate global gene silencing during aestivation in A. japonicus.展开更多
250 million people worldwide continue to be chronically infected with the virus.While patients may be treated with nucleoside/nucleotide analogues,this only suppresses HBV titre to sub-detection levels without elimina...250 million people worldwide continue to be chronically infected with the virus.While patients may be treated with nucleoside/nucleotide analogues,this only suppresses HBV titre to sub-detection levels without eliminating the persistent HBV covalently closed circular DNA(cccDNA)genome.As a result,HBV infection cannot be cured,and the virus reactivates when conditions are favorable.Interferons(IFNs)are cytokines known to induce powerful antiviral mechanisms that clear viruses from infected cells.They have been shown to induce cccDNA clearance,but their use in the treatment of HBV infection is limited as HBVtargeting immune cells are exhausted and HBV has evolved multiple mechanisms to evade and suppress IFN signalling.Thus,to fully utilize IFN-mediated intracellular mechanisms to effectively eliminate HBV,instead of direct IFN administration,novel strategies to sustain IFN-mediated anti-cccDNA and antiviral mechanisms need to be developed.This review will consolidate what is known about how IFNs act to achieve its intracellular antiviral effects and highlight the critical interferon-stimulated gene targets and effector mechanisms with potent anti-cccDNA functions.These include cccDNA degradation by APOBECs and cccDNA silencing and transcription repression by epigenetic modifications.In addition,the mechanisms that HBV employs to disrupt IFN signalling will be discussed.Drugs that have been developed or are in the pipeline for components of the IFN signalling pathway and HBV targets that detract IFN signalling mechanisms will also be identified and discussed for utility in the treatment of HBV infections.Together,these will provide useful insights into design strategies that specifically target cccDNA for the eradication of HBV.展开更多
Spinal cord injury that results in severe neurological disability is often incurable.The poor clinical outcome of spinal cord injury is mainly caused by the failure to reconstruct the injured neural circuits.Several i...Spinal cord injury that results in severe neurological disability is often incurable.The poor clinical outcome of spinal cord injury is mainly caused by the failure to reconstruct the injured neural circuits.Several intrinsic and extrinsic determinants contribute to this inability to reconnect.Epigenetic regulation acts as the driving force for multiple pathological and physiological processes in the central nervous system by modulating the expression of certain critical genes.Recent studies have demonstrated that post-SCI alteration of epigenetic landmarks is strongly associated with axon regeneration,glial activation and neurogenesis.These findings not only establish a theoretical foundation for further exploration of spinal cord injury,but also provide new avenues for the clinical treatment of spinal cord injury.This review focuses on the epigenetic regulation in axon regeneration and secondary spinal cord injury.Together,these discoveries are a selection of epigenetic-based prognosis biomarkers and attractive therapeutic targets in the treatment of spinal cord injury.展开更多
DNA methylation plays an important role in the epigenetic regulation of gene expression during plant growth,development,and polyploidization.However,there is still no distinct evidence in tobacco regarding the distrib...DNA methylation plays an important role in the epigenetic regulation of gene expression during plant growth,development,and polyploidization.However,there is still no distinct evidence in tobacco regarding the distribution of the methylation pattern and whether it contributes to qualitative characteristics.We studied the levels and patterns of methylation polymorphism at CCGG sites in 48 accessions of allotetraploid flue-cured tobacco,Nicotiana tabacum,using a methylation-sensitive amplified polymorphism(MSAP) technique.The results showed that methylation existed at a high level among tobacco accessions,among which 49.3% sites were methylated and 69.9% allelic sites were polymorphic.A cluster analysis revealed distinct patterns of geography-specific groups.In addition,three polymorphic sites significantly related to tobacco mosaic virus(TMV) resistance were explored.This suggests that tobacco breeders should pay more attention to epigenetic traits.展开更多
Reconstructed embryos derived from intersubspecies somatic cell nuclear transfer （SCNT） have poorer developmental potential than those from intrasubspecies SCNT. Based on our previous study that Holstein dairy bovi...Reconstructed embryos derived from intersubspecies somatic cell nuclear transfer （SCNT） have poorer developmental potential than those from intrasubspecies SCNT. Based on our previous study that Holstein dairy bovine （HD） mitochondrial DNA （mtDNA） haplotype compatibility between donor karyoplast and recipient cytoplast is crucial for SCNT embryo development, we performed intersubspecies SCNT using HD as donor karyoplast and Luxi yellow heifer （LY） as recipient cytoplast according to mtDNA haplotypes determined by polymerase chain reaction- restriction fragment length polymorphism （PCR-RFLP） analysis. The results demonstrated that intersubspecies mtDNA homotype SCNT embryos had higher pre- and post-implantation developmental competence than intrasubspecies mtDNA heterotype embryos as well as improved blastocyst reprogramming status, including normal H3K9 dimethylation pattern and promoter hypomethylation of pluripotent genes such as Oct4 and Sox2, suggesting that intersubspecies SCNT using LY oocytes maintains HD cloning efficiency and may reprogram HD nuclei to develop into a normal cloned animal ultimately. Our results indicated that karyoplast-cytoplast interactions and mtDNA haplotype compatibility may affect bovine intersubspecies SCNT efficiency. This study on bovine intersubspecies SCNT is valuable for understanding the mechanisms of mtDNA haplotype compatibility between karyoplast and cytoplast impacting the bovine SCNT efficiency, and provides an alternative and economic resource for HD cloning.展开更多
Epigenetic modifications have been observed as a decline in miRNA-21 expression and breast cancer stem cell(CSC)population after 3 cycles of standard chemotherapy.The epigenetic response(miRNAs expression)and CSCs are...Epigenetic modifications have been observed as a decline in miRNA-21 expression and breast cancer stem cell(CSC)population after 3 cycles of standard chemotherapy.The epigenetic response(miRNAs expression)and CSCs are also correlated in patients with Breast Cancer.In patients who tolerated chemotherapy well,miRNA-21(non-coding RNA)expression decreased significantly after three cycles of chemotherapy.The miRNA-21 expression in breast cancer tissue was quantified by quantitative PCR(real-time PCR)using the standard protocol.In addition,breast CSCs(CD44+/CD24-)were also decreased in these patients.The miRNA-21 regulates cell division,proliferation,and autophagy of cancerous cells(as it targets phosphatase and tensin homolog/AKT/transcription factor EB/programmed cell death 4/autophagy-related protein 5 and chemotherapy also produces similar effects),thereby contributing to these benefits.Therefore,when all of the targets on genes have been explored by mimic miRNA,chemotherapy combined with anti-miRNA21 therapy may prove useful in the care of cancer patients.展开更多
PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expr...PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular complexes involved in processes that are altered in cancer cells. For example, this oncogene has been found as part of the RNA polymerase Ⅱ complex, the splicing machinery and nutrient sensing machinery, although its role in these complexes remains unclear. More recently, the PDRG1 protein was found as an interaction target for the catalytic subunits of methionine adenosyltransferases. These enzymes synthesize S-adenosylmethionine, the methyl donor for, among others, epigenetic methylations that occur on the DNA and histones. In fact, downregulation of S-adenosylmethionine synthesis is the first functional effect directly ascribed to PDRG1. The existence of global DNA hypomethylation, together with increased PDRG1 expression, in many tumor cells highlights the importance of this interaction as one of the putative underlying causes for cell transformation. Here, we will review the accumulated knowledge on this oncogene, emphasizing the numerous aspects that remain to be explored.展开更多
Polycomb group（PcG） proteins are crucial epigenetic regulators conferring transcriptional memory to cell lineages.They assemble into multi-protein complexes,e.g.,Polycomb Repressive Complex 1 and 2（PRC1,PRC2）,whic...Polycomb group（PcG） proteins are crucial epigenetic regulators conferring transcriptional memory to cell lineages.They assemble into multi-protein complexes,e.g.,Polycomb Repressive Complex 1 and 2（PRC1,PRC2）,which are thought to act in a sequential manner to stably maintain gene repression.PRC2 induces histone H3 lysine 27（H3K27） trimethylation（H3K27me3）,which is subsequently read by PRCl that further catalyzes H2A monoubiquitination（H2Aub1）,creating a transcriptional silent chromatin conformation.PRC2 components are conserved in plants and have been extensively characterized in Arabidopsis.In contrast,PRCl composition and function are more diverged between animals and plants.Only more recently,PRC1 existence in plants has been documented.Here we review the aspects of plant specific and conserved PRC1 and highlight critical roles of PRC1 components in seed embryonic trait determinacy,shoot stem cell fate determinacy,and flower development in Arabidopsis.展开更多
Breast cancer has a relatively high mortality rate in women due to recurrence and metastasis. Increasing evidence has identified a rare population of cells with stem cell-like properties in breast cancer. These cells,...Breast cancer has a relatively high mortality rate in women due to recurrence and metastasis. Increasing evidence has identified a rare population of cells with stem cell-like properties in breast cancer. These cells, termed cancer stem cells （CSCs）, which have the capacity for self-renewal and differentiation, contribute significantly to tumor progression, recurrence, drug resistance and metastasis. Clarifying the mechanisms regulating breast CSCs has important implications for our understanding of breast cancer progression and therapeutics. A strong connection has been found between breast CSCs and epithelial mesenchymal transition （EMT）. In addition, recent studies suggest that the maintenance of the breast CSC phenotype is associated with epigenetic and metabolic regulation. In this review, we focus on recent discoveries about the connection between EMT and CSC, and advances made in under- standing the roles and mechanisms of epigenetic and metabolic reprogramming in controlling breast CSC properties.展开更多
基金supported by grants from the Major Projects of Health Science Research Foundation for Middle-Aged and Young Scientist of Fujian Province,China,No.2022ZQNZD01010010the National Natural Science Foundation of China,No.82371390Fujian Province Scientific Foundation,No.2023J01725(all to XC).
文摘The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.
基金supported by the National Natural Science Foundation of China(Nos.82271158,82301312,82071045,82101219,82071048).
文摘Hearing loss,which currently affects more than 430 million individuals globally and is projected to exceed 700 million by 2050,predominantly manifests as sensorineural hearing loss(SNHL),for which existing technologies such as hearing aids and cochlear implants fail to restore natural auditory function.Research focusing on protecting inner ear hair cells(HCs)from harmful factors through the regulation of epigenetic modifications has gained significant attention in otology for its role in regulating gene expression without altering the DNA sequence,suggesting potential strategies for preventing and treating SNHL.By synthesizing relevant studies on the inner ear,this review summarizes the emerging roles of histone modifications,DNA methylation,and noncoding RNAs in HC damage,with a focus on their therapeutic potential through epigenetic modulation.Moreover,this review examines the therapeutic potential of epigenetic regulation for the prevention and treatment of SNHL,emphasizing the application of small-molecule epigenetic compounds and their efficacy in modulating gene expression to preserve and restore auditory function.
基金supported by the National Natural Science Foundation of China,Nos.82071383,82371392(to BN)the Natural Science Foundation of Shandong Province of China(Key Project),No.ZR2020KH007(to BN)+1 种基金“Taishan Scholar Distinguished Expert Program”of Shandong Province,No.tstp20231257(to BN)Health Commission Science and Technology Plan Project of Jinan,No.2023-1-8(to YZ).
文摘Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.
基金supported by the National Natural Science Foundation of China(grant number 82373515 to J.L.).
文摘Radiation-induced lung injury(RILI)is a common complication of radiotherapy.Although berberine(BBR)has been suggested to be associated with reduced RILI incidence,the underlying mechanisms remain unknown.Here,we investigated whether the gut microbiota mediates the radioprotective effects of BBR using a C57BL/6 RILI mouse model with 20 Gy thoracic irradiation(n=6 per group).BBR(100 mg/kg)and inosine(INO,300 mg/kg)were administered orally in vivo.Antibiotic depletion and fecal microbiota transplantation were performed to assess microbiota dependence.Lung injury was assessed by histology,pulmonary function,and cytokine levels.Gut microbiota was analyzed by 16S rRNA sequencing,and metabolites were profiled using LC-MS/MS.Transcriptomic and epigenomic alterations were assessed by RNA sequencing,ATAC sequencing,and CUT&Tag analysis.Molecular docking and surface plasmon resonance were used to assess metabolite-protein interactions.We demonstrated that BBR alleviated RILI in a microbiota-dependent manner.BBR increased Akkermansia muciniphila abundance and metabolite INO levels.Mechanistically,INO was associated with reduced neuron navigator 3(NAV3)expression,accompanied by decreased chromatin accessibility and increased histone H3 lysine 27 trimethylation(H3K27me3)at the NAV3 locus.Together,these findings reveal a gut microbiota-mediated mechanism underlying BBR-mediated protection against RILI,and suggest microbiota-informed biomarkers for risk stratification.
基金Supported by The National Institute of Alcohol Abuse and Alcoholism grants AA014371 (to Joshi-Barve S),AA015970 (to McClain CJ), and Office of Dietary Supplements, NIH
文摘Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at many levels including nutrient intake,absorption,utilization,and excretion,and can lead to many nutritional disturbances and deficiencies.Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease(ALD).There is growing interest regarding epigenetic changes,including histone modifications that regulate gene expression during disease pathogenesis.Notably,modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation,and control gene transcription.This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD.The review is focused on four critical metabolites,namely,acetate,S-adenosylmethionine,nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD.
文摘BACKGROUND Pancreatic cancer(PC)is one of the deadliest malignancies with an alarming mortality rate.Despite significant advancement in diagnostics and therapeutics,early diagnosis remains elusive causing poor prognosis,marred by mutations and epigenetic modifications in key genes which contribute to disease progression.AIM To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley.METHODS A total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9(CA 19-9),tissue polypeptide specific antigen(TPS),carcinoembryonic antigen(CEA),vascular endothelial growth factor-A(VEGF-A),and epidermal growth factor receptor(EGFR).Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma(KRAS),Breast cancer type 2(BRCA-2),and deleted in pancreatic cancer-4(DPC-4)genes.However,epigenetic modifications(methylation of CpG islands)were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A(p16;CDKN2A),MutL homolog 1(hMLH1),and Ras association domain-containing protein 1(RASSF1A)genes.RESULTS We found significantly elevated levels of biological markers CA 19-9(P≤0.05),TPS(P≤0.05),CEA(P≤0.001),and VEGF(P≤0.001).Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12(16 subjects,P≤0.05),and 13(12 subjects,P≤0.05).However,we did not find a mutation in DPC-4(1203G>T)and BRCA-2(617delT)genes.Furthermore,epigenetic modification revealed that CpG methylation in 21(P≤0.05)and 4 subjects in the promoter regions of the p16 and hMLH1 gene,respectively.CONCLUSION In conclusion,CA 19-9,TPS,CEA,and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC.Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC.Additionally,methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.
文摘Background:Retinal pigment epithelium(RPE)is vital for the homeostasis of the subretina including photoreceptors and choroid.Interestingly,our previous results suggested that the recently discovered lactate receptor GPR81 is abundantly expressed in RPE.To date,only one previous study has shown that activating GPR81 could enhance DNA repair by activating HDAC1.Consequently,we investigated whether GPR81 exhibits epigenetic modification in the subretina by using GPR81−/−mice.Methods:GPR81−/−mice and wide type littermates were generated on a background of C57BL/6J mice.The thicknesses of their choroid were evaluated by immunohistochemistry.Meanwhile,Q-PCR,western blot and choroid sprout assay were performed.In vitro,primary retinal pigment epithelium(pRPE)cells were isolated from mice,and cultured for treatments.Results:The thickness of choroid was reduced in GPR81−/−mice compared to GPR81+/+mice,suggesting that GPR81 is important for the integrity of choroid.In the choroid sprout assay,lactate treated RPE/choroid complex showed a significant increase in angiogenesis compared to controls while lactate treated KO RPE/choroid complex showed no difference compared to their controls.For Q-PCR,most of the genes screened elevated their expression in GPR81−/−mice compared to WT mice,suggesting epigenetic modification may exist,which were confirmed by histone acetylation and HDACs activity assay.Conclusions:Taking together,the lactate receptor GPR81 in RPE is very important for maintaining homeostasis of the subretina.This novel discovery sheds new light on the relationship between metabolism and epigenetic modification.
基金This work is funded by National Natural Science Foundation of China(No.81773466)to W.H,and by Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular Disease(No.DXWL2023-06)to W.X.
文摘Epigenetic modifications modulate conformational structure of chromatin and consequently gene expression by enzyme-mediated chemical modifications of DNA and histones.The activities of epigenetic modifying enzymes depend on many co-substrates and cofactors,such as 2-oxoglutarate(2-OG),iron,S-adenosylmethionine(SAM),nicotinamide adenine dinucleotide(NAD+),flavin adenine dinucleotide(FAD),and acetyl-CoA.These factors are inter-connecting molecules that integrate cellular nutrient metabolism and redox homeostasis,two key regulators of cell proliferation,cell survival,and cell functions.Dysregulation of such delicate regulatory network has been implicated in many pathological conditions and also been increasingly recognized as an emerging mechanism responsible for environmental pollutant-induced adverse effects.In this review,we first summarize DNA and histone modifying enzymes and their essential factors,then discuss the metabolic sources and the redox regulatory roles of these enzymatic factors,and finally elaborate the mechanisms of how targeting such factors by environmental pollutants influences epigenetic regulation and perturbs cellular functions.
基金supported by the Tianjin Stomatological Hospital MD and PhD Key Program(No.2019BSZD11)Periodontal Key Discipline Project of Tianjin Stomatological Hospital(2022P02)+1 种基金the Science and Technology Project of Tianjin Health Commission(No.ZC20039)the High-level Talents in the Medical/Health Care Industry-Young Medical Elites(No.TJSQNYXXR-D2-114).
文摘Objective To investigate the treatment effect of the histone demethylase inhibitor GSK-J4,a small molecule that inhibits the demethylase activity of Jumonji domain-containing protein 3(JMJD3),in the treatment of periodontitis.Methods Gingival tissues from patients with moderate to severe chronic periodontitis and healthy controls were collected to evaluate JMJD3 expression via real-time quantitative reverse transcription PCR(RT-qPCR)and immunohistochemistry(IHC).Next,Sprague–Dawley(SD)rats were used to investigate the effect of GSK-J4 in vivo.The experimental periodontitis model was induced by upper first molar ligation and gingival sulcus injection of Porphyromonas gingivalis.The rats were divided into a healthy group,a periodontitis group,periodontitis plus GSK-J4 treatment groups(P+GSK-J415 mg/kg or 25 mg/kg),and a periodontitis plus dimethyl sulfoxide(DMSO)group(P+DMSO).After 4 weeks,maxillary molar segments were assessed via micro-computed tomography(CT)and hematoxylin and eosin(HE)staining.Serum tumor necrosis factor-α(TNF-α)levels were measured by enzyme-linked immunosorbent assay(ELISA).Results Higher expression of the Jmjd3 gene and JMJD3 protein was detected in human inflamed gingiva than in healthy gingiva(P<0.05).GSK-J4 administration reversed alveolar bone absorption[i.e.,reduced alveolar bone crest(ABC)-cementoenamel junction(CEJ)distance],reduced inflammatory cell accumulation at the crest of the alveolar bone,and alleviated serum TNF-αlevels in rats with periodontitis.Moreover,the number of H3K27me3-positive nuclei was greater in model rats treated with GSK J4 than in model rats.Conclusions The histone demethylase inhibitor GSK-J4 attenuated periodontal bone loss and inflammation in a rat periodontitis model by targeting JMJD3.
基金Supported by National Natural Science Foundation of China,No.30271450,No.30471955,No.30672365 and No.81172516
文摘MicroRNAs are evolutionarily conserved small noncoding RNA molecules encoded by eukaryotic genomic DNA,and function in post-transcriptional regulation of gene expression via base-pairing with complementary sequences in target mRNAs,resulting in translational repression or degradation of target mRNAs.They represent one of the major types of epigenetic modification and play important roles in all aspects of cellular activities.Altered expression of microRNAs has been found in various human diseases including cancer.Many efforts have been made to discover the characteristic microRNA expression profiles,to understand the roles of aberrantly expressed microRNAs and underlying mechanisms in different cancers.With the application of DNA microarray,real-time quantitative polymerase chain reaction and other molecular biology techniques,increasing evidence has been accumulated which reveal that aberrant microRNAs can be detected not only intracellularly within the cancer cells,but also extracellularly in plasma of patients,postulating the potential of aberrant microRNAs as promising diagnostic/prognostic markers and attracting therapeutic targets.This review is intended to provide the most recent advances in microRNA studies in one of the most common cancers,colorectal cancer,especially the identification of those specifically altered microRNAs in colorectal cancer,validation for their relevance to clinical pathological parameters of patients,functional analyses and potential applications of these microRNAs.
基金This study was supported by grants from the National 973 Basic Research Program of China，the National Nature Science Foundation of China，Foundation of Program for New Century Excellent Talents in University (NCET-11-0311) to Yi F，Program for Changjiang Scholars and Innovative Research Team in University，the Special Financial Grant from the China Postdoctoral Science Foundation，the China Postdoctoral Science Foundation，the Shandong Province Post-doctoral Innovation Foundation
文摘Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediated epigenetic processes in the development of cardio-cerebrovascular injury. HDACs are a family of enzymes to balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. To date, 18 mammalian HDACs are identified and grouped into four classes based on similarity to yeast orthologs. The zinc-dependent HDAC family currently consists of 11 members divided into three classes （class I, II, and IV） on the basis of structure, sequence homology, and domain organization. In comparison, class III HDACs （also known as the sirtuins） are composed of a family of NAD＋-dependent protein-modifying enzymes related to the Sir2 gene. HDAC inhibitors are a group of compounds that block HDAC activities typically by binding to the zinc-containing catalytic domain of HDACs and have displayed an- ti-inflammatory and antifibrotic effects in the cardio-cerebrovascular system. In this review, we summarize the current knowledge about classifications, functions of HDACs and their roles and regulatory mechanisms in the cardio-cerebrovascular system. Pharmacological tar- geting of HDAC-mediated epigenetic processes may open new therapeutic avenues for the treatment of CCVD.
基金Supported by the National Key Technology Research and Development Program(No.2006AA10A411)the Agricultural Seed Project of Shandong Province
文摘The sea cucumber, Apostichopusjaponicus, undergoes aestivation to improve survival during periods of high-temperature. During aestivation, the metabolic rate is depressed to reduce the consumption of reserved energy. We evaluated the role of epigenetic modification on global gene silencing during metabolic rate depression in the sea cucumber. We compared the expression of epigenetic modifiers in active and aestivating sea cucumbers. The expression of three genes involved in DNA methylation and chromatin remodeling （DNA （cytosine-5）-methyltransferase l, Methyl-CpG-binding domain protein 2）, and Chromodomain-helicase-DNA-binding protein 5） was significantly higher during aestivation （Days 20 and 40）. Similarly, we observed an increase in the expression of genes involved in histone acetylation （Histone deacetylase 3） and Histone-binding protein RBBP4） during the early （Days 5 and 10） and late phases （Days 20 and 40） of aestivation. There was no change in the expression of KAT2B, a histone acetyltransferase. However, the expression of histone methylation associated modifiers （Histone-arginine methyltransferase CARMER and Histone-lysine N-methyltransferase MLL5） was significantly higher after 5 d in the aestivating group. The results suggest that the expression of epigenetic modifiers involved in DNA methylation, chromatin remodeling, histone acetylation, and histone methylation is upregulated during aestivation. We hypothesize that these changes regulate global gene silencing during aestivation in A. japonicus.
文摘250 million people worldwide continue to be chronically infected with the virus.While patients may be treated with nucleoside/nucleotide analogues,this only suppresses HBV titre to sub-detection levels without eliminating the persistent HBV covalently closed circular DNA(cccDNA)genome.As a result,HBV infection cannot be cured,and the virus reactivates when conditions are favorable.Interferons(IFNs)are cytokines known to induce powerful antiviral mechanisms that clear viruses from infected cells.They have been shown to induce cccDNA clearance,but their use in the treatment of HBV infection is limited as HBVtargeting immune cells are exhausted and HBV has evolved multiple mechanisms to evade and suppress IFN signalling.Thus,to fully utilize IFN-mediated intracellular mechanisms to effectively eliminate HBV,instead of direct IFN administration,novel strategies to sustain IFN-mediated anti-cccDNA and antiviral mechanisms need to be developed.This review will consolidate what is known about how IFNs act to achieve its intracellular antiviral effects and highlight the critical interferon-stimulated gene targets and effector mechanisms with potent anti-cccDNA functions.These include cccDNA degradation by APOBECs and cccDNA silencing and transcription repression by epigenetic modifications.In addition,the mechanisms that HBV employs to disrupt IFN signalling will be discussed.Drugs that have been developed or are in the pipeline for components of the IFN signalling pathway and HBV targets that detract IFN signalling mechanisms will also be identified and discussed for utility in the treatment of HBV infections.Together,these will provide useful insights into design strategies that specifically target cccDNA for the eradication of HBV.
基金supported by the National Natural Science Foundation of China,Nos.81701225(to BYZ),81874254(to PYC),81571189 and 81772353(to Saijilafu)the Excellent Youth Grant of Science and Technology Department of Jilin Province of China,No.20190103077JH(to BYZ)the Bethune Project of Jilin University of China,No.2015312(to BYZ)
文摘Spinal cord injury that results in severe neurological disability is often incurable.The poor clinical outcome of spinal cord injury is mainly caused by the failure to reconstruct the injured neural circuits.Several intrinsic and extrinsic determinants contribute to this inability to reconnect.Epigenetic regulation acts as the driving force for multiple pathological and physiological processes in the central nervous system by modulating the expression of certain critical genes.Recent studies have demonstrated that post-SCI alteration of epigenetic landmarks is strongly associated with axon regeneration,glial activation and neurogenesis.These findings not only establish a theoretical foundation for further exploration of spinal cord injury,but also provide new avenues for the clinical treatment of spinal cord injury.This review focuses on the epigenetic regulation in axon regeneration and secondary spinal cord injury.Together,these discoveries are a selection of epigenetic-based prognosis biomarkers and attractive therapeutic targets in the treatment of spinal cord injury.
基金supported by the Program for High-Quality Tobacco Development of China (No. [2010]221)the Foundation of Science and Technology of Guizhou Province (No. J[2010]2251)the Program for Guizhou Tobacco Science of China (No. 200910)
文摘DNA methylation plays an important role in the epigenetic regulation of gene expression during plant growth,development,and polyploidization.However,there is still no distinct evidence in tobacco regarding the distribution of the methylation pattern and whether it contributes to qualitative characteristics.We studied the levels and patterns of methylation polymorphism at CCGG sites in 48 accessions of allotetraploid flue-cured tobacco,Nicotiana tabacum,using a methylation-sensitive amplified polymorphism(MSAP) technique.The results showed that methylation existed at a high level among tobacco accessions,among which 49.3% sites were methylated and 69.9% allelic sites were polymorphic.A cluster analysis revealed distinct patterns of geography-specific groups.In addition,three polymorphic sites significantly related to tobacco mosaic virus(TMV) resistance were explored.This suggests that tobacco breeders should pay more attention to epigenetic traits.
基金This work was supported by the grants from the National High-Tech R&D Program of China(No.2007AA100502)the National Science and Technology Major Project of China (No.2008ZX08007-004)the National Natural Science Foundation of China(No.30770242)
文摘Reconstructed embryos derived from intersubspecies somatic cell nuclear transfer （SCNT） have poorer developmental potential than those from intrasubspecies SCNT. Based on our previous study that Holstein dairy bovine （HD） mitochondrial DNA （mtDNA） haplotype compatibility between donor karyoplast and recipient cytoplast is crucial for SCNT embryo development, we performed intersubspecies SCNT using HD as donor karyoplast and Luxi yellow heifer （LY） as recipient cytoplast according to mtDNA haplotypes determined by polymerase chain reaction- restriction fragment length polymorphism （PCR-RFLP） analysis. The results demonstrated that intersubspecies mtDNA homotype SCNT embryos had higher pre- and post-implantation developmental competence than intrasubspecies mtDNA heterotype embryos as well as improved blastocyst reprogramming status, including normal H3K9 dimethylation pattern and promoter hypomethylation of pluripotent genes such as Oct4 and Sox2, suggesting that intersubspecies SCNT using LY oocytes maintains HD cloning efficiency and may reprogram HD nuclei to develop into a normal cloned animal ultimately. Our results indicated that karyoplast-cytoplast interactions and mtDNA haplotype compatibility may affect bovine intersubspecies SCNT efficiency. This study on bovine intersubspecies SCNT is valuable for understanding the mechanisms of mtDNA haplotype compatibility between karyoplast and cytoplast impacting the bovine SCNT efficiency, and provides an alternative and economic resource for HD cloning.
基金Supported by SERB:Department of Science and Technology,New Delhi,No. NPDF:SERB 2015/000322
文摘Epigenetic modifications have been observed as a decline in miRNA-21 expression and breast cancer stem cell(CSC)population after 3 cycles of standard chemotherapy.The epigenetic response(miRNAs expression)and CSCs are also correlated in patients with Breast Cancer.In patients who tolerated chemotherapy well,miRNA-21(non-coding RNA)expression decreased significantly after three cycles of chemotherapy.The miRNA-21 expression in breast cancer tissue was quantified by quantitative PCR(real-time PCR)using the standard protocol.In addition,breast CSCs(CD44+/CD24-)were also decreased in these patients.The miRNA-21 regulates cell division,proliferation,and autophagy of cancerous cells(as it targets phosphatase and tensin homolog/AKT/transcription factor EB/programmed cell death 4/autophagy-related protein 5 and chemotherapy also produces similar effects),thereby contributing to these benefits.Therefore,when all of the targets on genes have been explored by mimic miRNA,chemotherapy combined with anti-miRNA21 therapy may prove useful in the care of cancer patients.
基金support by the Ministerio Educación y CienciaMinisterio de Economía y Competitividad of Spain(until June 2013)
文摘PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular complexes involved in processes that are altered in cancer cells. For example, this oncogene has been found as part of the RNA polymerase Ⅱ complex, the splicing machinery and nutrient sensing machinery, although its role in these complexes remains unclear. More recently, the PDRG1 protein was found as an interaction target for the catalytic subunits of methionine adenosyltransferases. These enzymes synthesize S-adenosylmethionine, the methyl donor for, among others, epigenetic methylations that occur on the DNA and histones. In fact, downregulation of S-adenosylmethionine synthesis is the first functional effect directly ascribed to PDRG1. The existence of global DNA hypomethylation, together with increased PDRG1 expression, in many tumor cells highlights the importance of this interaction as one of the putative underlying causes for cell transformation. Here, we will review the accumulated knowledge on this oncogene, emphasizing the numerous aspects that remain to be explored.
基金supported by the French Centre National de la Recherche Scientifique(CNRS)the French Agence Nationale de la Recherche(ANR-08-BLAN- 0200-CSD7)
文摘Polycomb group（PcG） proteins are crucial epigenetic regulators conferring transcriptional memory to cell lineages.They assemble into multi-protein complexes,e.g.,Polycomb Repressive Complex 1 and 2（PRC1,PRC2）,which are thought to act in a sequential manner to stably maintain gene repression.PRC2 induces histone H3 lysine 27（H3K27） trimethylation（H3K27me3）,which is subsequently read by PRCl that further catalyzes H2A monoubiquitination（H2Aub1）,creating a transcriptional silent chromatin conformation.PRC2 components are conserved in plants and have been extensively characterized in Arabidopsis.In contrast,PRCl composition and function are more diverged between animals and plants.Only more recently,PRC1 existence in plants has been documented.Here we review the aspects of plant specific and conserved PRC1 and highlight critical roles of PRC1 components in seed embryonic trait determinacy,shoot stem cell fate determinacy,and flower development in Arabidopsis.
基金supported by the Thousand Young Talents Program of Chinathe National Natural Science Foundation of China(No.81472455)the Fundamental Research Funds for the Central Universities of China
文摘Breast cancer has a relatively high mortality rate in women due to recurrence and metastasis. Increasing evidence has identified a rare population of cells with stem cell-like properties in breast cancer. These cells, termed cancer stem cells （CSCs）, which have the capacity for self-renewal and differentiation, contribute significantly to tumor progression, recurrence, drug resistance and metastasis. Clarifying the mechanisms regulating breast CSCs has important implications for our understanding of breast cancer progression and therapeutics. A strong connection has been found between breast CSCs and epithelial mesenchymal transition （EMT）. In addition, recent studies suggest that the maintenance of the breast CSC phenotype is associated with epigenetic and metabolic regulation. In this review, we focus on recent discoveries about the connection between EMT and CSC, and advances made in under- standing the roles and mechanisms of epigenetic and metabolic reprogramming in controlling breast CSC properties.
