Cell fate determination as a fundamental question in cell biology has been extensively studied at different regulatory levels for many years.However,the mechanisms of multilevel regulation of cell fate determination r...Cell fate determination as a fundamental question in cell biology has been extensively studied at different regulatory levels for many years.However,the mechanisms of multilevel regulation of cell fate determination remain unclear.Recently,we have proposed an Epigenome-Metabolome-Epigenome(E-M-E)signaling cascade model to describe the cross-over cooperation during mouse somatic cell reprogramming.In this review,we summarize the broad roles of E-M-E signaling cascade in different cell biological processes,including cell differentiation and dedifferentiation,cell specialization,cell proliferation,and cell pathologic processes.Precise E-M-E signaling cascades are critical in these cell biological processes,and it is of worth to explore each step of E-M-E signaling cascade.E-M-E signaling cascade model sheds light on and may open a window to explore the mechanisms of multilevel regulation of cell biological processes.展开更多
DNA methylation participates in regulating the expression of coding and non-coding regions in plants. To investigate the association between DNA methylation and pathogen infection, we used whole-genome bisulfite seque...DNA methylation participates in regulating the expression of coding and non-coding regions in plants. To investigate the association between DNA methylation and pathogen infection, we used whole-genome bisulfite sequencing to survey temporal DNA methylation changes in rice after infection with the rice blast fungus Magnaporthe oryzae. In contrast to previous findings in Arabidopsis, global DNA methylation levels in rice increased slightly after rice blast infection. We identified over 38,000 differentially methylated regions(DMRs), and hypermethylated DMRs far outnumbered hypomethylated DMRs. Most DMRs were located in transposable element regions. Using transcriptome analysis, we identified 8830 differentially expressed genes(DEGs) after 1, 3, and 5 days of infection. Over one-third of DEGs, most of which were CHH-type DMRs, were associated with DMRs. Functional analysis of the CHH DMR-DEGs indicated their involvement in many important biological processes, including cell communication and response to external stimulus. The transcription of many NBS-LRR family genes was affected by changes in DNA methylation, suggesting that DNA methylation plays essential roles in the response of rice to M. oryzae infection. More broadly, the DNA methylation analysis presented here sheds light on epigenomic involvement in plant defense against fungal pathogens.展开更多
Although the exact etiology of inflammatory bowel disease(IBD)remains unclear,exaggerated immune response in genetically predisposed individuals has been reported.Th1 and Th17 cells mediate IBD development.Macrophages...Although the exact etiology of inflammatory bowel disease(IBD)remains unclear,exaggerated immune response in genetically predisposed individuals has been reported.Th1 and Th17 cells mediate IBD development.Macrophages produce IL-12 and IL-23 that share p40 subunit encoded by IL12B gene as heteromer partner to drive Th1 and Th17 differentiation.The available animal and human data strongly support the pathogenic role of IL-12/IL-23 in IBD development and suggest that blocking p40 might be the potential strategy for IBD treatment.Furthermore,aberrant alteration of some cytokines expression via epigenetic mechanisms is involved in pathogenesis o f IBD.In this study,we analyzed core promoter region of IL12B gene and investigated whether IL12B expression could be regulated through targeted epigenetic modification with gene editing technology.Transcription activator-like effectors(TALEs)are widely used in the field of genome editing and can specifically target DNA sequence in the host genome.We synthesized the TALE DNA-binding domains that target the promoter of human IL12B gene and fused it with the functional catalytic domains of epigenetic enzymes.Transient expression of these engineered enzymes demonstrated that the TALE-DNMT3A targeted the selected IL12B promoter region,induced loci-specific DNA methylation,and down-regulated IL-12B expression in various human cell lines.Collectively,our data suggested that epigenetic editing of IL12B through methylating DNA on its promoter might be developed as a potential therapeutic strategy for IBD treatment.展开更多
Epigenetics-mediated breeding(epibreeding)involves engineering crop traits and stress responses through the targeted manipulation of key epigenetic features to enhance agricultural productivity.While conventional bree...Epigenetics-mediated breeding(epibreeding)involves engineering crop traits and stress responses through the targeted manipulation of key epigenetic features to enhance agricultural productivity.While conventional breeding methods raise concerns about reduced genetic diversity,epibreeding propels crop improvement through epigenetic variations that regulate gene expression,ultimately impacting crop yield.Epigenetic regulation in crops encompasses various modes,including histone modification,DNA modification,RNA modification,non-coding RNA,and chromatin remodeling.This review summarizes the epigenetic mechanisms underlying major agronomic traits in maize and identifies candidate epigenetic landmarks in the maize breeding process.We propose a valuable strategy for improving maize yield through epibreeding,combining CRISPR/Cas-based epigenome editing technology and Synthetic Epigenetics(SynEpi).Finally,we discuss the challenges and opportunities associated with maize trait improvement through epibreeding.展开更多
The complexity of the epigenome landscape and transcriptional regulation is significantly increased during plant polyploidization,which drives genome evolution and contributes to the increased adaptability to diverse ...The complexity of the epigenome landscape and transcriptional regulation is significantly increased during plant polyploidization,which drives genome evolution and contributes to the increased adaptability to diverse environments.However,a comprehensive epigenome map of Brassica napus is still unavailable.In this study,we performed integrative analysis of five histone modifications,RNA polymerase Ⅱ CCU-pancy,DNA methylation,and transcriptomes in two B.napus lines(2063A and B409),and established global maps of regulatory elements,chromatin states,and their dynamics for the whole genome(including the An and Cn subgenomes)in four tissue types(young leaf,flower bud,silique,and root)of these two lines.Approximately 65.8% of the genome was annotated with different epigenomic signals.Compared with the Cn subgenome,the An subgenome possesses a higher level of active epigenetic marks and lower level of repressive epigenetic marks.Genes from subgenome-unique regions contribute to the major differences between the An and Cn subgenomes.Asymmetric histone modifications between homeologous gene pairs reflect their biased expression patterns.We identified a novel bivalent chromatin state(with H3K4me1 and H3K27me3)in B.napus that is associated with tissue-specific gene expression.Furthermore,we observed that different types of duplicated genes have discrepant patterns of histone modification and DNA methylation levels.Collectively,our findings provide a valuable epigenetic resource for allopolyploid plants.展开更多
Colorectal cancer(CRC)is a common malignant tumor with a high mortality rate worldwide.Advanced CRC often leads to liver metastasis,which has a poor prognosis,highlighting the need to investigate the underlying mechan...Colorectal cancer(CRC)is a common malignant tumor with a high mortality rate worldwide.Advanced CRC often leads to liver metastasis,which has a poor prognosis,highlighting the need to investigate the underlying mechanisms.Omics,encompassing genomics,epigenomics,transcriptomics,proteomics,metabolomics,and microbiomics,enables comprehensive molecular analysis of cells and tissues.Tumor-omics research has advanced rapidly,with growing attention on CRC-related omics.However,systematic reviews on omics research specific to colorectal cancer liver metastasis(CRLM)are limited.This review summarizes the current status and progress of multi-omics research on CRLM and discusses the application of multi-omics technologies in basic research and the significant clinical implications.展开更多
Epigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment outcome.To determine the potential contribution of DNA methylation alterations to tu...Epigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment outcome.To determine the potential contribution of DNA methylation alterations to tumor phenotype in non-small cell lung cancer(NSCLC)in both smoker and never-smoker patients,we performed genome-wide profiling of DNA methylation in 17 primary NSCLC tumors and 10 matched normal lung samples using the complementary assays,methylated DNA immunoprecipitation sequencing(MeDIP-seq)and methylation sensitive restric-tion enzyme sequencing(MRE-seq).We reported recurrent methylation changes in the promoters of several genes,many previously implicated in cancer,including FAM83A and SEPT9(hy-pomethylation),as well as PCDH7,NKX2-1,and SOX17(hypermethylation).Although many methylation changes between tumors and their paired normal samples were shared across patients,several were specific to a particular smoking status.For example,never-smokers displayed a greater proportion of hypomethylated differentially methylated regions(hypoDMRs)and a greater number of recurrently hypomethylated promoters,including those of ASPSCRI,TOP2A,DPP9,and USP39,all previously linked to cancer.Changes outside of promoters were also widespread and often recurrent,particularly methylation loss over repetitive elements,highly enriched for ERV1 subfamilies.Recurrent hypoDMRs were enriched for several transcription factor binding motifs,often for genes involved in signaling and cell proliferation.For example,71%of recurrent promoter hypoDMRs contained a motif for NKX2-1.Finally,the majority of DMRs were located within an active chromatin state in tissues profiled using the Roadmap Epigenomics data,suggesting that methylation changes may contribute to altered regulatory programs through the adaptation of cell type-specific expression programs.展开更多
Nasopharyngeal carcinoma(NPC)has been a focus of medical research for more than 100 years,with significant interest emerging over the last 58 years following the identification of the link between the disease and Epst...Nasopharyngeal carcinoma(NPC)has been a focus of medical research for more than 100 years,with significant interest emerging over the last 58 years following the identification of the link between the disease and Epstein-Barr virus(EBV)infection.NPC possesses several distinctive characteristics among human cancers,notably its well-documented global epidemiology,which reveals localized high-incidence regions primarily in Southeast Asia,particularly in the Southern provinces of China near the Pearl river,as well as in Greenland and North Africa.Epidemiological data indicate a marked male predominance,early disease onset,and a nearly 100%prevalence of latent EBV infection in the tumors.Due to lack of consistent pattern of cancer-related mutations in NPC genomes and excessive DNA-methylation in the tumor cells,NPC can be considered"an epigenetic cancer".Despite extensive researches,convincing biological explanations for these unique characteristics remain elusive.Recently,suggestive evidence has been published that specific local variants of EBV may represent major high risk factors.In spite of tumor and virus specific immunity,it has not been possible to use this for improved treatment.Ongoing studies on the role of the local microflora and tumor microenvironment are essential for a comprehensive understanding of host-EBV-tumor interactions.Ultimately,this knowledge aims to enhance diagnosis,disease fractionation,treatment strategies,and potentially prevention of NPC.展开更多
BACKGROUND Aberrant methylation is common during the initiation and progression of colorectal cancer(CRC),and detecting these changes that occur during early adenoma(ADE)formation and CRC progression has clinical valu...BACKGROUND Aberrant methylation is common during the initiation and progression of colorectal cancer(CRC),and detecting these changes that occur during early adenoma(ADE)formation and CRC progression has clinical value.AIM To identify potential DNA methylation markers specific to ADE and CRC.METHODS Here,we performed SeqCap targeted bisulfite sequencing and RNA-seq analysis of colorectal ADE and CRC samples to profile the epigenomic-transcriptomic landscape.RESULTS Comparing 22 CRC and 25 ADE samples,global methylation was higher in the former,but both showed similar methylation patterns regarding differentially methylated gene positions,chromatin signatures,and repeated elements.High-grade CRC tended to exhibit elevated methylation levels in gene promoter regions compared to those in low-grade CRC.Combined with RNA-seq gene expression data,we identified 14 methylation-regulated differentially expressed genes,of which only AGTR1 and NECAB1 methylation had prognostic significance.CONCLUSION Our results suggest that genome-wide alterations in DNA methylation occur during the early stages of CRC and demonstrate the methylation signatures associated with colorectal ADEs and CRC,suggesting prognostic biomarkers for CRC.展开更多
BACKGROUND Unhealthy maternal diet leads to heavy metal exposures from the consumption of ultra-processed foods that may impact gene behavior across generations,creating conditions for the neurodevelopmental disorders...BACKGROUND Unhealthy maternal diet leads to heavy metal exposures from the consumption of ultra-processed foods that may impact gene behavior across generations,creating conditions for the neurodevelopmental disorders known as autism and attention deficit/hyperactivity disorder(ADHD).Children with these disorders have difficulty metabolizing and excreting heavy metals from their bloodstream,and the severity of their symptoms correlates with the heavy metal levels measured in their blood.Psychiatrists may play a key role in helping parents reduce their ultra-processed food and dietary heavy metal intake by providing access to effective nutritional epigenetics education.AIM To test the efficacy of nutritional epigenetics instruction in reducing parental ultra-processed food intake.METHODS The study utilized a semi-randomized test and control group pretest-posttest pilot study design with participants recruited from parents having a learning-disabled child with autism or ADHD.Twenty-two parents who met the inclusion criteria were randomly selected to serve in the test(n=11)or control(n=11)group.The test group participated in the six-week online nutritional epigenetics tutorial,while the control group did not.The efficacy of the nutritional epigenetics instruction was determined by measuring changes in parent diet and attitude using data derived from an online diet survey administered to the participants during the pre and post intervention periods.Diet intake scores were derived for both ultra-processed and whole/organic foods.Paired sample t-tests were conducted to determine any differences in mean diet scores within each group.RESULTS There was a significant difference in the diet scores of the test group between the pre-and post-intervention periods.The parents in the test group significantly reduced their intake of ultra-processed foods with a preintervention diet score of 70(mean=5.385,SD=2.534)and a post-intervention diet score of 113(mean=8.692,SD=1.750)and the paired t-test analysis showing a significance of P<0.001.The test group also significantly increased their consumption of whole and/or organic foods with a pre-intervention diet score of 100(mean=5.882,SD=2.472)and post-intervention diet score of 121(mean=7.118,SD=2.390)and the paired t-test analysis showing a significance of P<0.05.CONCLUSION Here we show nutritional epigenetics education can be used to reduce ultra-processed food intake and improve attitude among parents having learning-disabled children with autism or ADHD.展开更多
Intensively developed in the last few years, single-cell sequencing technologies now present numerous advantages over traditional sequencing methods for solving the problems of biological heterogeneity and low quantit...Intensively developed in the last few years, single-cell sequencing technologies now present numerous advantages over traditional sequencing methods for solving the problems of biological heterogeneity and low quantities of available biological materials. The application of single-cell sequencing technologies has profoundly changed our understanding of a series of biological phenomena, including gene transcription, embryo development, and carcinogenesis. However, before single-cell sequencing technologies can be used extensively, researchers face the serious challenge of overcoming inherent issues of high amplification bias, low accuracy and repro- ducibility. Here, we simply summarize the techniques used for single-cell isolation, and review the current technologies used in single-cell genomic, transcriptomic, and epigenomic sequencing, We discuss the merits, defects, and scope of application of single-cell sequencing technologies and then speculate on the direction of future developments.展开更多
The clustered regularly interspaced short palindromic repeats （CRISPR）/Cas9 system, a simple and efficient tool for genome editing, has experienced rapid progress in its technology and applicability in the past two ...The clustered regularly interspaced short palindromic repeats （CRISPR）/Cas9 system, a simple and efficient tool for genome editing, has experienced rapid progress in its technology and applicability in the past two years. Here, we review the recent advances in CRISPR/Cas9 technology and the ways that have been adopted to expand our capacity for precise genome manipulation. First, we introduce the mechanism of CRISPR/Cas9, including its biochemical and structural implications. Second, we highlight the latest improvements in the CRISPR/Cas9 system, especially Cas9 protein modifications for customization. Third, we review its current applications, in which the versatile CRISPR/Cas9 system was employed to edit the genome, epigenome, or RNA of various organisms. Although CRISPR/Cas9 allows convenient genome editing accompanied by many benefits, we should not ignore the significant ethical and biosafety concerns that it raises. Finally, we discuss the prospective applications and challenges of several promising techniques adapted from CRISPR/Cas9.展开更多
It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epid...It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epidemiologists alike has led to the extensive characterization of this tumor virus, Kaposi's sarcoma-associated herpesvirus(KSHV; also known as human herpesvirus 8(HHV-8)), and its associated diseases. Here we review the current knowledge of KSHV biology and pathogenesis, with a particular emphasis on new and exciting advances in the field of epigenetics. We also discuss the development and practicality of various cell culture and animal model systems to study KSHV replication and pathogenesis.展开更多
Genetic,epigenetic,and metabolic alterations are all hallmarks of cancer.However,the epigenome and metabolome are both highly complex and dynamic biological networks in vivo.The interplay between the epigenome and met...Genetic,epigenetic,and metabolic alterations are all hallmarks of cancer.However,the epigenome and metabolome are both highly complex and dynamic biological networks in vivo.The interplay between the epigenome and metabolome contributes to a biological system that is responsive to the tumor microenvironment and possesses a wealth of unknown biomarkers and targets of cancer therapy.From this perspective,we first review the state of high-throughput biological data acquisition(i.e.multiomics data)and analysis(i.e.computational tools)and then propose a conceptual in silico metabolic and epigenetic regulatory network(MER-Net)that is based on these current high-throughput methods.The conceptual MER-Net is aimed at linking metabolomic and epigenomic networks through observation of biological processes,omics data acquisition,analysis of network information,and integration with validated database knowledge.Thus,MER-Net could be used to reveal new potential biomarkers and therapeutic targets using deep learning models to integrate and analyze large multiomics networks.We propose that MER-Net can serve as a tool to guide integrated metabolomics and epigenomics research or can be modified to answer other complex biological and clinical questions using multiomics data.展开更多
Diabetes mellitus rightly regarded as a silent-epidemic is continually on the rise and estimated to have a global prevalence of 6.4 % as of 2010.Diabetes during pregnancy is a well known risk factor for congenital ano...Diabetes mellitus rightly regarded as a silent-epidemic is continually on the rise and estimated to have a global prevalence of 6.4 % as of 2010.Diabetes during pregnancy is a well known risk factor for congenital anomalies in various organ systems that contribute to neonatal mortality,including cardiovascular,gastrointestinal,genitourinary and neurological systems,among which the neural tube defects are frequently reported.Over the last two to three decades,several groups around the world have focussed on identifying the molecular cues and cellular changes resulting in altered gene expression and the morphological defects and in diabetic pregnancy.In recent years,the focus has gradually shifted to looking at pre-programmed changes and activation of epigenetic mechanisms that cause altered gene expression.While several theories such as oxidative stress,hypoxia,and apoptosis triggered due to hyperglycemic conditions have been proposed and proven for being the cause for these defects,the exact mechanism or the link between how high glucose can alter gene expression/transcriptome and activate epigenetic mechanisms is largely unknown.Although preconceptual control of diabetes,(i.e.,managing glu-cose levels during pregnancy),and in utero therapies has been proposed as an effective solution for managing diabetes during pregnancy,the impact that a fluctuating glycemic index can have on foetal development has not been evaluated in detail.A tight glycemic control started before pregnancy has shown to reduce the incidence of congenital abnormalities in diabetic mothers.On the other hand,a tight glycemic control after organogenesis and embryogenesis have begun may prove insufficient to prevent or reverse the onset of congenital defects.The importance of determining the extent to which glycemic levels in diabetic mothers should be regulated is critical as foetal hypoglycemia has also been shown to be teratogenic.Finally,the major question remaining is if this whole issue is negligible and not worthy of investigation as the efficient management of diabetes during pregnancy is well in place in many countries.展开更多
Cholangiocarcinoma(CCA)is a notoriously lethal epith-elial cancer originating from the biliary system.As radical resection offers a poor success rate and limited effective adjuvant modalities exist in its advanced sta...Cholangiocarcinoma(CCA)is a notoriously lethal epith-elial cancer originating from the biliary system.As radical resection offers a poor success rate and limited effective adjuvant modalities exist in its advanced stage,the disease leads to a fairly poor prognosis.As the incidence of CCA is increasing,although the mortality rate remains stable,and few other definite etiologies have yet to be established,renewing our knowledge of its fundamental carcinogenesis is advisable.The latest advances in molecular carcinogenesis have highlighted the roles of epigenetic perturbations and cancer-related inflammation in CCA.This review focuses on the reciprocal effects between aberrant DNA methylation and inflammatory microenvironment in CCA.展开更多
The objective of this review is to discuss the changes in human biology and physiology that occur when humans, who evolved on Earth for millions of years, now are subjected to space flight for extended periods of time...The objective of this review is to discuss the changes in human biology and physiology that occur when humans, who evolved on Earth for millions of years, now are subjected to space flight for extended periods of time, and how detailing such changes associated with space flight could help better understand risks for loss of health on Earth. Space programs invest heavily in the selection and training of astronauts. They also are investing in maintaining the health of astronauts, both for extensive stays in low earth orbit on ISS, and in preparation for deep space missions in the future. This effort is critical for the success of such missions as the N is small and the tasks needed to be performed in a hostile environment are complex and demanding. However, space is a unique environment, devoid of many of the “boundary conditions” that shaped human evolution (e.g. 1 g environment, magnetic fields, background radiation, oxygen, water, etc). Therefore, for humans to be successful in space, we need to learn to adapt and minimize the impact of an altered environment on human health. Conversely, we can also learn considerably from this altered environment for life on earth. The question is, are we getting the maximal information from life in space to learn about like on earth? The answer is likely No, and as such, our “Return on Investment” is not as great as it could be. Even though the number of astronauts is not large, what we can learn from them could help shape new questions for research focused on health for those on earth, as well is contribute to “precision health” from the study of astronaut diversity. This latter effort would contribute to both the health of astronauts identifying risks, as well as contribute to health on earth via better understanding of the human genome and epigenome, as well as factors contributing to risk for diseases on earth, particularly as individuals age and regulatory systems become altered. Better use of the International Space Station, and similar platforms in the future, could provide critical insights in aging-associated risks for loss of health on Earth, as well as promote new approaches to using precision medicine to overcome threats to health while in space. To achieve this goal will likely require advanced approaches to collecting such information and use of more systems biology, systems physiology approaches to integrate the information.展开更多
There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene expression.However,the role of metabolites in activating the key gene regulatory networ...There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene expression.However,the role of metabolites in activating the key gene regulatory network for specialization of germ cell lineage remains largely unknown.Here,we identified some cellular metabolites with significant changes by untargeted metabolomics between mouse epiblast-like cells(EpiLCs)and primordial germ cell-like cells(PGCLCs).More importantly,we found that inhibition of glutaminolysis by bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES)impeded PGCLC specialization,but the impediment could be rescued by addition ofα-ketoglutarate(αKG),the intermediate metabolite of oxidative phosphorylation and glutaminolysis.Moreover,adding aKG alone to the PGCLC medium accelerated the PGCLC specialization through promoting H3 K27 me3 demethylation.Thus,our study reveals the importance of metabolite aKG in the germ cell fate determination and highlights the essential role of cellular metabolism in shaping the cell identities through epigenetic events.展开更多
According to the developmental origin of health and disease concept,the risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early developme...According to the developmental origin of health and disease concept,the risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development.In particular,maternal obesity and neonatal accelerated growth predispose offspring to overweight and type 2 diabetes(T2 D) in adulthood.This concept mainly relies on the developmental plasticity of adipose tissue and pancreatic β-cell programming in response to suboptimal milieu during the perinatal period.These changes result in unhealthy hypertrophic adipocytes with decreased capacity to store fat,lowgrade inflammation and loss of insulin-producing pancreatic β-cells.Over the past years,many efforts have been made to understand how maternal obesity induces long-lasting adipose tissue and pancreatic β-cell dysfunction in offspring and what are the molecular basis of the transgenerational inheritance of T2 D.In particular,rodent studies have shed light on the role of epigenetic mechanisms in linking maternal nutritional manipulations to the risk for T2 D in adulthood.In this review,we discuss epigenetic adipocyte and β-cell remodeling during development in the progeny of obese mothers and the persistence of these marks as a basis of obesity and T2 D predisposition.展开更多
Although a relationship between epigenetics and aging phenotypic changes has been established,a theoretical explanation of the intrinsic connection between the epigenetics and aging is lacking.In this essay,we propose...Although a relationship between epigenetics and aging phenotypic changes has been established,a theoretical explanation of the intrinsic connection between the epigenetics and aging is lacking.In this essay,we propose that epigenetic recording of varied cell environment and complex history could be an origin of cellular aging.Through epigenetic modifications,the environment and historical events can induce the chromatin template into an activated or repressive accessible structure,thereby shaping the DNA template into a spectrum of chromatin states.The inner nature of diversity and conflicts born by the cell environment and its historical events are hence recorded into the chromatin template.This could result in a dissipated spectrum of the chromatin state and chaos in overall gene expression.An unavoidable degradation of epigenome entropy,similar to Shannon entropy,would be consequently induced.The resultant disorder in epigenome,characterized by corrosion of epigenome entropy as reflected in chromatin template,can be stably memorized and propagated through cell division.Furthermore,the hysteretic nature of epigenetics responding to the emerging environment could exacerbate the degradation of epigenome entropy.As well as stochastic errors,we propose that outside entropy(or chaos) derived from the varied environment and complex cell history,gradually input and imprinted into the chromatin via epigenetic modifications,would lead inevitably to cellular aging,the extent of which could be aggravated by hysteresis of epigenetics without error erasing and correction.展开更多
基金financially supported by the National Key Research and Development Program of China (2017YFA0106300)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030505)+6 种基金the National Natural Science Foundation projects of China (2017YFA0102900, 2019YFA09004500, 2017YFC1001602, 2016YFA0100300, 2018YFA0107100)the National Natural Science Foundation projects of China (92157202, 32025010, 31801168, 31900614, 31970709, 81901275, 32070729, 32100619, 32170747)the Key Research Program of Frontier Sciences, CAS (QYZDB-SSW-SMC001)International Cooperation Program (154144KYSB20200006)Guangdong Province Science and Technology Program (2020B1212060052, 2018A030313825, 2018GZR110103002, 2020A1515011200, 2020A1515010919, 2020A1515011410, 2021A1515012513)Guangzhou Science and Technology Program (201807010067, 202002030277, 202102021250, 202102020827, 202102080066), Open Research Program of Key Laboratory of Regenerative Biology, CAS (KLRB201907, KLRB202014)CAS Youth Innovation Promotion Association (to Y. W. and K. C.)
文摘Cell fate determination as a fundamental question in cell biology has been extensively studied at different regulatory levels for many years.However,the mechanisms of multilevel regulation of cell fate determination remain unclear.Recently,we have proposed an Epigenome-Metabolome-Epigenome(E-M-E)signaling cascade model to describe the cross-over cooperation during mouse somatic cell reprogramming.In this review,we summarize the broad roles of E-M-E signaling cascade in different cell biological processes,including cell differentiation and dedifferentiation,cell specialization,cell proliferation,and cell pathologic processes.Precise E-M-E signaling cascades are critical in these cell biological processes,and it is of worth to explore each step of E-M-E signaling cascade.E-M-E signaling cascade model sheds light on and may open a window to explore the mechanisms of multilevel regulation of cell biological processes.
基金supported by the Natural Science Foundation of Fujian Province(2018J06006)National Key Research and Development Program of China(2016YFD0300700)+4 种基金National Natural Science Foundation of China(31770156)State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops(SKL2018006)the Program for New Century Excellent Talents of Fujian Province Universitythe Pre-eminent Youth Fund and Distinguished Young Scholars of Fujian Provincesupported by the Supercomputing Center at the College of Plant Protection of Fujian Agriculture and Forestry University。
文摘DNA methylation participates in regulating the expression of coding and non-coding regions in plants. To investigate the association between DNA methylation and pathogen infection, we used whole-genome bisulfite sequencing to survey temporal DNA methylation changes in rice after infection with the rice blast fungus Magnaporthe oryzae. In contrast to previous findings in Arabidopsis, global DNA methylation levels in rice increased slightly after rice blast infection. We identified over 38,000 differentially methylated regions(DMRs), and hypermethylated DMRs far outnumbered hypomethylated DMRs. Most DMRs were located in transposable element regions. Using transcriptome analysis, we identified 8830 differentially expressed genes(DEGs) after 1, 3, and 5 days of infection. Over one-third of DEGs, most of which were CHH-type DMRs, were associated with DMRs. Functional analysis of the CHH DMR-DEGs indicated their involvement in many important biological processes, including cell communication and response to external stimulus. The transcription of many NBS-LRR family genes was affected by changes in DNA methylation, suggesting that DNA methylation plays essential roles in the response of rice to M. oryzae infection. More broadly, the DNA methylation analysis presented here sheds light on epigenomic involvement in plant defense against fungal pathogens.
基金The study was supported by the National Natural Science Foundation of China(No.81270468).
文摘Although the exact etiology of inflammatory bowel disease(IBD)remains unclear,exaggerated immune response in genetically predisposed individuals has been reported.Th1 and Th17 cells mediate IBD development.Macrophages produce IL-12 and IL-23 that share p40 subunit encoded by IL12B gene as heteromer partner to drive Th1 and Th17 differentiation.The available animal and human data strongly support the pathogenic role of IL-12/IL-23 in IBD development and suggest that blocking p40 might be the potential strategy for IBD treatment.Furthermore,aberrant alteration of some cytokines expression via epigenetic mechanisms is involved in pathogenesis o f IBD.In this study,we analyzed core promoter region of IL12B gene and investigated whether IL12B expression could be regulated through targeted epigenetic modification with gene editing technology.Transcription activator-like effectors(TALEs)are widely used in the field of genome editing and can specifically target DNA sequence in the host genome.We synthesized the TALE DNA-binding domains that target the promoter of human IL12B gene and fused it with the functional catalytic domains of epigenetic enzymes.Transient expression of these engineered enzymes demonstrated that the TALE-DNMT3A targeted the selected IL12B promoter region,induced loci-specific DNA methylation,and down-regulated IL-12B expression in various human cell lines.Collectively,our data suggested that epigenetic editing of IL12B through methylating DNA on its promoter might be developed as a potential therapeutic strategy for IBD treatment.
基金supported by funding from the National Key R&D Program of China(2023ZD0407304)the Sci-Tech Innovation 2030 Agenda(2022ZD0115703)Fundamental Research Funds for Central Non-Profit of Chinese Academy of Agricultural Sciences(Y2023PT20).
文摘Epigenetics-mediated breeding(epibreeding)involves engineering crop traits and stress responses through the targeted manipulation of key epigenetic features to enhance agricultural productivity.While conventional breeding methods raise concerns about reduced genetic diversity,epibreeding propels crop improvement through epigenetic variations that regulate gene expression,ultimately impacting crop yield.Epigenetic regulation in crops encompasses various modes,including histone modification,DNA modification,RNA modification,non-coding RNA,and chromatin remodeling.This review summarizes the epigenetic mechanisms underlying major agronomic traits in maize and identifies candidate epigenetic landmarks in the maize breeding process.We propose a valuable strategy for improving maize yield through epibreeding,combining CRISPR/Cas-based epigenome editing technology and Synthetic Epigenetics(SynEpi).Finally,we discuss the challenges and opportunities associated with maize trait improvement through epibreeding.
基金This work was financially supported by the National Natural Science Foundation of China(31930032,31701163,31771422,and 31771402)the National Key Research and Development Program of China(2016YFD0101300 and 2018YFC1604000)+3 种基金the China Postdoctoral Science Foundation(2017M612479)the Fundamental Research Funds for the Central Universities(2662018py033)the open funds of the National Key Laboratory of Crop Genetic Improvement(ZK201906)the Program for Modern Agricultural Industrial Technology System of China(grant no.CARS-12).
文摘The complexity of the epigenome landscape and transcriptional regulation is significantly increased during plant polyploidization,which drives genome evolution and contributes to the increased adaptability to diverse environments.However,a comprehensive epigenome map of Brassica napus is still unavailable.In this study,we performed integrative analysis of five histone modifications,RNA polymerase Ⅱ CCU-pancy,DNA methylation,and transcriptomes in two B.napus lines(2063A and B409),and established global maps of regulatory elements,chromatin states,and their dynamics for the whole genome(including the An and Cn subgenomes)in four tissue types(young leaf,flower bud,silique,and root)of these two lines.Approximately 65.8% of the genome was annotated with different epigenomic signals.Compared with the Cn subgenome,the An subgenome possesses a higher level of active epigenetic marks and lower level of repressive epigenetic marks.Genes from subgenome-unique regions contribute to the major differences between the An and Cn subgenomes.Asymmetric histone modifications between homeologous gene pairs reflect their biased expression patterns.We identified a novel bivalent chromatin state(with H3K4me1 and H3K27me3)in B.napus that is associated with tissue-specific gene expression.Furthermore,we observed that different types of duplicated genes have discrepant patterns of histone modification and DNA methylation levels.Collectively,our findings provide a valuable epigenetic resource for allopolyploid plants.
基金supported by grants from the Natural Science Foundation of Chongqing(Grant No.CSTB2024NSCQ-MSX0478).
文摘Colorectal cancer(CRC)is a common malignant tumor with a high mortality rate worldwide.Advanced CRC often leads to liver metastasis,which has a poor prognosis,highlighting the need to investigate the underlying mechanisms.Omics,encompassing genomics,epigenomics,transcriptomics,proteomics,metabolomics,and microbiomics,enables comprehensive molecular analysis of cells and tissues.Tumor-omics research has advanced rapidly,with growing attention on CRC-related omics.However,systematic reviews on omics research specific to colorectal cancer liver metastasis(CRLM)are limited.This review summarizes the current status and progress of multi-omics research on CRLM and discusses the application of multi-omics technologies in basic research and the significant clinical implications.
基金supported in part by the Siteman Cancer Center Precision Medicine Pathway(Grant No.T32CA113275)Erica C.Pehrsson is supported by a Postdoctoral Fellowship from the American Cancer Society(Grant No.PF-17-201-01)+6 种基金Erica C.Pehrsson,Jennifer A.Karlow,and Ting Wang are supported by the National Institutes of Health[Grant Nos.R01HG007354(National Human Genome Research Institute)R01HG007175(National Human Genome Research Institute)R01ES024992(National Institute of Environmental Health Sciences)U01CA200060(National Cancer Institute)U24ES026699(National Institute of Environmental Health Sciences)U01HG009391(National Human Genome Research Institute)]the American Cancer Society(Grant No.RSG-14-049-01-DMC).
文摘Epigenetic alterations are widespread in cancer and can complement genetic alterations to influence cancer progression and treatment outcome.To determine the potential contribution of DNA methylation alterations to tumor phenotype in non-small cell lung cancer(NSCLC)in both smoker and never-smoker patients,we performed genome-wide profiling of DNA methylation in 17 primary NSCLC tumors and 10 matched normal lung samples using the complementary assays,methylated DNA immunoprecipitation sequencing(MeDIP-seq)and methylation sensitive restric-tion enzyme sequencing(MRE-seq).We reported recurrent methylation changes in the promoters of several genes,many previously implicated in cancer,including FAM83A and SEPT9(hy-pomethylation),as well as PCDH7,NKX2-1,and SOX17(hypermethylation).Although many methylation changes between tumors and their paired normal samples were shared across patients,several were specific to a particular smoking status.For example,never-smokers displayed a greater proportion of hypomethylated differentially methylated regions(hypoDMRs)and a greater number of recurrently hypomethylated promoters,including those of ASPSCRI,TOP2A,DPP9,and USP39,all previously linked to cancer.Changes outside of promoters were also widespread and often recurrent,particularly methylation loss over repetitive elements,highly enriched for ERV1 subfamilies.Recurrent hypoDMRs were enriched for several transcription factor binding motifs,often for genes involved in signaling and cell proliferation.For example,71%of recurrent promoter hypoDMRs contained a motif for NKX2-1.Finally,the majority of DMRs were located within an active chromatin state in tissues profiled using the Roadmap Epigenomics data,suggesting that methylation changes may contribute to altered regulatory programs through the adaptation of cell type-specific expression programs.
文摘Nasopharyngeal carcinoma(NPC)has been a focus of medical research for more than 100 years,with significant interest emerging over the last 58 years following the identification of the link between the disease and Epstein-Barr virus(EBV)infection.NPC possesses several distinctive characteristics among human cancers,notably its well-documented global epidemiology,which reveals localized high-incidence regions primarily in Southeast Asia,particularly in the Southern provinces of China near the Pearl river,as well as in Greenland and North Africa.Epidemiological data indicate a marked male predominance,early disease onset,and a nearly 100%prevalence of latent EBV infection in the tumors.Due to lack of consistent pattern of cancer-related mutations in NPC genomes and excessive DNA-methylation in the tumor cells,NPC can be considered"an epigenetic cancer".Despite extensive researches,convincing biological explanations for these unique characteristics remain elusive.Recently,suggestive evidence has been published that specific local variants of EBV may represent major high risk factors.In spite of tumor and virus specific immunity,it has not been possible to use this for improved treatment.Ongoing studies on the role of the local microflora and tumor microenvironment are essential for a comprehensive understanding of host-EBV-tumor interactions.Ultimately,this knowledge aims to enhance diagnosis,disease fractionation,treatment strategies,and potentially prevention of NPC.
基金the National Natural Science Foundation of China,No.81960504the“Xingdian Talents”Support Project of Yunnan Province,No.RLQB20200002+2 种基金the Medical Discipline Reserve Talents of Yunnan Province,No.H-2018015the Applied Basic Research Projects-Union Foundation of Kunming Medical University,No.2017FE467(-132)the Talent Introduction Project of Hubei Polytechnic University,No.21xjz34R。
文摘BACKGROUND Aberrant methylation is common during the initiation and progression of colorectal cancer(CRC),and detecting these changes that occur during early adenoma(ADE)formation and CRC progression has clinical value.AIM To identify potential DNA methylation markers specific to ADE and CRC.METHODS Here,we performed SeqCap targeted bisulfite sequencing and RNA-seq analysis of colorectal ADE and CRC samples to profile the epigenomic-transcriptomic landscape.RESULTS Comparing 22 CRC and 25 ADE samples,global methylation was higher in the former,but both showed similar methylation patterns regarding differentially methylated gene positions,chromatin signatures,and repeated elements.High-grade CRC tended to exhibit elevated methylation levels in gene promoter regions compared to those in low-grade CRC.Combined with RNA-seq gene expression data,we identified 14 methylation-regulated differentially expressed genes,of which only AGTR1 and NECAB1 methylation had prognostic significance.CONCLUSION Our results suggest that genome-wide alterations in DNA methylation occur during the early stages of CRC and demonstrate the methylation signatures associated with colorectal ADEs and CRC,suggesting prognostic biomarkers for CRC.
文摘BACKGROUND Unhealthy maternal diet leads to heavy metal exposures from the consumption of ultra-processed foods that may impact gene behavior across generations,creating conditions for the neurodevelopmental disorders known as autism and attention deficit/hyperactivity disorder(ADHD).Children with these disorders have difficulty metabolizing and excreting heavy metals from their bloodstream,and the severity of their symptoms correlates with the heavy metal levels measured in their blood.Psychiatrists may play a key role in helping parents reduce their ultra-processed food and dietary heavy metal intake by providing access to effective nutritional epigenetics education.AIM To test the efficacy of nutritional epigenetics instruction in reducing parental ultra-processed food intake.METHODS The study utilized a semi-randomized test and control group pretest-posttest pilot study design with participants recruited from parents having a learning-disabled child with autism or ADHD.Twenty-two parents who met the inclusion criteria were randomly selected to serve in the test(n=11)or control(n=11)group.The test group participated in the six-week online nutritional epigenetics tutorial,while the control group did not.The efficacy of the nutritional epigenetics instruction was determined by measuring changes in parent diet and attitude using data derived from an online diet survey administered to the participants during the pre and post intervention periods.Diet intake scores were derived for both ultra-processed and whole/organic foods.Paired sample t-tests were conducted to determine any differences in mean diet scores within each group.RESULTS There was a significant difference in the diet scores of the test group between the pre-and post-intervention periods.The parents in the test group significantly reduced their intake of ultra-processed foods with a preintervention diet score of 70(mean=5.385,SD=2.534)and a post-intervention diet score of 113(mean=8.692,SD=1.750)and the paired t-test analysis showing a significance of P<0.001.The test group also significantly increased their consumption of whole and/or organic foods with a pre-intervention diet score of 100(mean=5.882,SD=2.472)and post-intervention diet score of 121(mean=7.118,SD=2.390)and the paired t-test analysis showing a significance of P<0.05.CONCLUSION Here we show nutritional epigenetics education can be used to reduce ultra-processed food intake and improve attitude among parents having learning-disabled children with autism or ADHD.
基金supported by the fund from the National High Technology Research and Development Program of China to Z.Sun (No.2012AA02A202)
文摘Intensively developed in the last few years, single-cell sequencing technologies now present numerous advantages over traditional sequencing methods for solving the problems of biological heterogeneity and low quantities of available biological materials. The application of single-cell sequencing technologies has profoundly changed our understanding of a series of biological phenomena, including gene transcription, embryo development, and carcinogenesis. However, before single-cell sequencing technologies can be used extensively, researchers face the serious challenge of overcoming inherent issues of high amplification bias, low accuracy and repro- ducibility. Here, we simply summarize the techniques used for single-cell isolation, and review the current technologies used in single-cell genomic, transcriptomic, and epigenomic sequencing, We discuss the merits, defects, and scope of application of single-cell sequencing technologies and then speculate on the direction of future developments.
基金supported by the grant from the Major State Basic Research Development Program of China(Nos.2012CB517902 and 2012CB517904)the Fundamental Research Funds for the Central Universities(No.14QNJJ042)Special Research Program of National Health and Family Planning Commission of China(No.201302002)
文摘The clustered regularly interspaced short palindromic repeats （CRISPR）/Cas9 system, a simple and efficient tool for genome editing, has experienced rapid progress in its technology and applicability in the past two years. Here, we review the recent advances in CRISPR/Cas9 technology and the ways that have been adopted to expand our capacity for precise genome manipulation. First, we introduce the mechanism of CRISPR/Cas9, including its biochemical and structural implications. Second, we highlight the latest improvements in the CRISPR/Cas9 system, especially Cas9 protein modifications for customization. Third, we review its current applications, in which the versatile CRISPR/Cas9 system was employed to edit the genome, epigenome, or RNA of various organisms. Although CRISPR/Cas9 allows convenient genome editing accompanied by many benefits, we should not ignore the significant ethical and biosafety concerns that it raises. Finally, we discuss the prospective applications and challenges of several promising techniques adapted from CRISPR/Cas9.
基金supported by National Institutes of Health grant R01DE016680 to Fanxiu Zhu and F31CA183250 to Denis Avey
文摘It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epidemiologists alike has led to the extensive characterization of this tumor virus, Kaposi's sarcoma-associated herpesvirus(KSHV; also known as human herpesvirus 8(HHV-8)), and its associated diseases. Here we review the current knowledge of KSHV biology and pathogenesis, with a particular emphasis on new and exciting advances in the field of epigenetics. We also discuss the development and practicality of various cell culture and animal model systems to study KSHV replication and pathogenesis.
基金supported by the National Natural Science Foundation of China(81890994,31871343)National Key Research and Development Program of China(2017YFA0505503,2018YFB0704304,2018YFA0801402)+1 种基金the WBE Liver Fibrosis Foundation(CFHPC 2020021)the Beijing Dongcheng District outstanding talent funding project and the Beijing Undergraduate Training Programs for Innovation and Entrepreneurship(202010023046)。
文摘Genetic,epigenetic,and metabolic alterations are all hallmarks of cancer.However,the epigenome and metabolome are both highly complex and dynamic biological networks in vivo.The interplay between the epigenome and metabolome contributes to a biological system that is responsive to the tumor microenvironment and possesses a wealth of unknown biomarkers and targets of cancer therapy.From this perspective,we first review the state of high-throughput biological data acquisition(i.e.multiomics data)and analysis(i.e.computational tools)and then propose a conceptual in silico metabolic and epigenetic regulatory network(MER-Net)that is based on these current high-throughput methods.The conceptual MER-Net is aimed at linking metabolomic and epigenomic networks through observation of biological processes,omics data acquisition,analysis of network information,and integration with validated database knowledge.Thus,MER-Net could be used to reveal new potential biomarkers and therapeutic targets using deep learning models to integrate and analyze large multiomics networks.We propose that MER-Net can serve as a tool to guide integrated metabolomics and epigenomics research or can be modified to answer other complex biological and clinical questions using multiomics data.
文摘Diabetes mellitus rightly regarded as a silent-epidemic is continually on the rise and estimated to have a global prevalence of 6.4 % as of 2010.Diabetes during pregnancy is a well known risk factor for congenital anomalies in various organ systems that contribute to neonatal mortality,including cardiovascular,gastrointestinal,genitourinary and neurological systems,among which the neural tube defects are frequently reported.Over the last two to three decades,several groups around the world have focussed on identifying the molecular cues and cellular changes resulting in altered gene expression and the morphological defects and in diabetic pregnancy.In recent years,the focus has gradually shifted to looking at pre-programmed changes and activation of epigenetic mechanisms that cause altered gene expression.While several theories such as oxidative stress,hypoxia,and apoptosis triggered due to hyperglycemic conditions have been proposed and proven for being the cause for these defects,the exact mechanism or the link between how high glucose can alter gene expression/transcriptome and activate epigenetic mechanisms is largely unknown.Although preconceptual control of diabetes,(i.e.,managing glu-cose levels during pregnancy),and in utero therapies has been proposed as an effective solution for managing diabetes during pregnancy,the impact that a fluctuating glycemic index can have on foetal development has not been evaluated in detail.A tight glycemic control started before pregnancy has shown to reduce the incidence of congenital abnormalities in diabetic mothers.On the other hand,a tight glycemic control after organogenesis and embryogenesis have begun may prove insufficient to prevent or reverse the onset of congenital defects.The importance of determining the extent to which glycemic levels in diabetic mothers should be regulated is critical as foetal hypoglycemia has also been shown to be teratogenic.Finally,the major question remaining is if this whole issue is negligible and not worthy of investigation as the efficient management of diabetes during pregnancy is well in place in many countries.
基金Supported by an NIH K01 Grant Award(DK078532) to Dr.DeMorrow
文摘Cholangiocarcinoma(CCA)is a notoriously lethal epith-elial cancer originating from the biliary system.As radical resection offers a poor success rate and limited effective adjuvant modalities exist in its advanced stage,the disease leads to a fairly poor prognosis.As the incidence of CCA is increasing,although the mortality rate remains stable,and few other definite etiologies have yet to be established,renewing our knowledge of its fundamental carcinogenesis is advisable.The latest advances in molecular carcinogenesis have highlighted the roles of epigenetic perturbations and cancer-related inflammation in CCA.This review focuses on the reciprocal effects between aberrant DNA methylation and inflammatory microenvironment in CCA.
文摘The objective of this review is to discuss the changes in human biology and physiology that occur when humans, who evolved on Earth for millions of years, now are subjected to space flight for extended periods of time, and how detailing such changes associated with space flight could help better understand risks for loss of health on Earth. Space programs invest heavily in the selection and training of astronauts. They also are investing in maintaining the health of astronauts, both for extensive stays in low earth orbit on ISS, and in preparation for deep space missions in the future. This effort is critical for the success of such missions as the N is small and the tasks needed to be performed in a hostile environment are complex and demanding. However, space is a unique environment, devoid of many of the “boundary conditions” that shaped human evolution (e.g. 1 g environment, magnetic fields, background radiation, oxygen, water, etc). Therefore, for humans to be successful in space, we need to learn to adapt and minimize the impact of an altered environment on human health. Conversely, we can also learn considerably from this altered environment for life on earth. The question is, are we getting the maximal information from life in space to learn about like on earth? The answer is likely No, and as such, our “Return on Investment” is not as great as it could be. Even though the number of astronauts is not large, what we can learn from them could help shape new questions for research focused on health for those on earth, as well is contribute to “precision health” from the study of astronaut diversity. This latter effort would contribute to both the health of astronauts identifying risks, as well as contribute to health on earth via better understanding of the human genome and epigenome, as well as factors contributing to risk for diseases on earth, particularly as individuals age and regulatory systems become altered. Better use of the International Space Station, and similar platforms in the future, could provide critical insights in aging-associated risks for loss of health on Earth, as well as promote new approaches to using precision medicine to overcome threats to health while in space. To achieve this goal will likely require advanced approaches to collecting such information and use of more systems biology, systems physiology approaches to integrate the information.
基金supported by grants from the National Natural Science Foundation of China(No.31871445 and No.31501211)the National Key R&D program of China(No.2017YFC1001302 and No.2016YFA0503300)。
文摘There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene expression.However,the role of metabolites in activating the key gene regulatory network for specialization of germ cell lineage remains largely unknown.Here,we identified some cellular metabolites with significant changes by untargeted metabolomics between mouse epiblast-like cells(EpiLCs)and primordial germ cell-like cells(PGCLCs).More importantly,we found that inhibition of glutaminolysis by bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide(BPTES)impeded PGCLC specialization,but the impediment could be rescued by addition ofα-ketoglutarate(αKG),the intermediate metabolite of oxidative phosphorylation and glutaminolysis.Moreover,adding aKG alone to the PGCLC medium accelerated the PGCLC specialization through promoting H3 K27 me3 demethylation.Thus,our study reveals the importance of metabolite aKG in the germ cell fate determination and highlights the essential role of cellular metabolism in shaping the cell identities through epigenetic events.
文摘According to the developmental origin of health and disease concept,the risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development.In particular,maternal obesity and neonatal accelerated growth predispose offspring to overweight and type 2 diabetes(T2 D) in adulthood.This concept mainly relies on the developmental plasticity of adipose tissue and pancreatic β-cell programming in response to suboptimal milieu during the perinatal period.These changes result in unhealthy hypertrophic adipocytes with decreased capacity to store fat,lowgrade inflammation and loss of insulin-producing pancreatic β-cells.Over the past years,many efforts have been made to understand how maternal obesity induces long-lasting adipose tissue and pancreatic β-cell dysfunction in offspring and what are the molecular basis of the transgenerational inheritance of T2 D.In particular,rodent studies have shed light on the role of epigenetic mechanisms in linking maternal nutritional manipulations to the risk for T2 D in adulthood.In this review,we discuss epigenetic adipocyte and β-cell remodeling during development in the progeny of obese mothers and the persistence of these marks as a basis of obesity and T2 D predisposition.
基金Project supported by the National Key R&D Program of China(No.2017YFA0605001)the National Natural Science Foundation of China(Nos.21876011 and 91547207)the Fund for Innovative Research Group of the National Natural Science Foundation of China(No.51721093)
文摘Although a relationship between epigenetics and aging phenotypic changes has been established,a theoretical explanation of the intrinsic connection between the epigenetics and aging is lacking.In this essay,we propose that epigenetic recording of varied cell environment and complex history could be an origin of cellular aging.Through epigenetic modifications,the environment and historical events can induce the chromatin template into an activated or repressive accessible structure,thereby shaping the DNA template into a spectrum of chromatin states.The inner nature of diversity and conflicts born by the cell environment and its historical events are hence recorded into the chromatin template.This could result in a dissipated spectrum of the chromatin state and chaos in overall gene expression.An unavoidable degradation of epigenome entropy,similar to Shannon entropy,would be consequently induced.The resultant disorder in epigenome,characterized by corrosion of epigenome entropy as reflected in chromatin template,can be stably memorized and propagated through cell division.Furthermore,the hysteretic nature of epigenetics responding to the emerging environment could exacerbate the degradation of epigenome entropy.As well as stochastic errors,we propose that outside entropy(or chaos) derived from the varied environment and complex cell history,gradually input and imprinted into the chromatin via epigenetic modifications,would lead inevitably to cellular aging,the extent of which could be aggravated by hysteresis of epigenetics without error erasing and correction.
