Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents

Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults.Pathogenic factors,such as oxidative stress,an increase in acetylcholinesterase activity,mitochondrial dysfunction,genotoxicity,and neuroinflammation are present in this syndrome,which leads to neurodegeneration.Neurodegenerative pathologies such as Alzheimer’s disease are considered late-onset diseases caused by the complex combination of genetic,epigenetic,and environmental factors.There are two main types of Alzheimer’s disease,known as familial Alzheimer’s disease(onset<65 years)and late-onset or sporadic Alzheimer’s disease(onset≥65 years).Patients with familial Alzheimer’s disease inherit the disease due to rare mutations on the amyloid precursor protein(APP),presenilin 1 and 2(PSEN1 and PSEN2)genes in an autosomaldominantly fashion with closely 100%penetrance.In contrast,a different picture seems to emerge for sporadic Alzheimer’s disease,which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology.Importantly,the fundamental pathophysiological mechanisms driving Alzheimer’s disease are interfaced with epigenetic dysregulation.However,the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer’s disease or following injury or stroke in humans.In recent years,there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer’s disease.Through epigenetic mechanisms,such as DNA methylation,non-coding RNAs,histone modification,and chromatin conformation regulation,natural compounds appear to exert neuroprotective effects.While we do not purport to cover every in this work,we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer’s disease-related genes.

Large-scale loss-of-function perturbations reveal a comprehensive epigenetic regulatory network in breast cancer

Objective:Epigenetic abnormalities have a critical role in breast cancer by regulating gene expression;however,the intricate interrelationships and key roles of approximately 400 epigenetic regulators in breast cancer remain elusive.It is important to decipher the comprehensive epigenetic regulatory network in breast cancer cells to identify master epigenetic regulators and potential therapeutic targets.Methods:We employed high-throughput sequencing-based high-throughput screening(HTS^(2))to effectively detect changes in the expression of 2,986 genes following the knockdown of 400 epigenetic regulators.Then,bioinformatics analysis tools were used for the resulting gene expression signatures to investigate the epigenetic regulations in breast cancer.Results:Utilizing these gene expression signatures,we classified the epigenetic regulators into five distinct clusters,each characterized by specific functions.We discovered functional similarities between BAZ2B and SETMAR,as well as CLOCK and CBX3.Moreover,we observed that CLOCK functions in a manner opposite to that of HDAC8 in downstream gene regulation.Notably,we constructed an epigenetic regulatory network based on the gene expression signatures,which revealed 8 distinct modules and identified 10 master epigenetic regulators in breast cancer.Conclusions:Our work deciphered the extensive regulation among hundreds of epigenetic regulators.The identification of 10 master epigenetic regulators offers promising therapeutic targets for breast cancer treatment.

Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease

BACKGROUND Prevalence of hepatocellular carcinoma(HCC)is increasing,especially in patients with metabolic dysfunctionassociated steatotic liver disease(MASLD).AIM To investigate rifaximin(RIF)effects on epigenetic/autophagy markers in animals.METHODS Adult Sprague-Dawley rats were randomly assigned(n=8,each)and treated from 5-16 wk:Control[standard diet,water plus gavage with vehicle(Veh)],HCC[high-fat choline deficient diet(HFCD),diethylnitrosamine(DEN)in drinking water and Veh gavage],and RIF[HFCD,DEN and RIF(50 mg/kg/d)gavage].Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained.RESULTS All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis,and cirrhosis,but three RIF-group did not develop HCC.Comparing animals who developed HCC with those who did not,miR-122,miR-34a,tubulin alpha-1c(Tuba-1c),metalloproteinases-2(Mmp2),and metalloproteinases-9(Mmp9)were significantly higher in the HCC-group.The opposite occurred with Becn1,coactivator associated arginine methyltransferase-1(Carm1),enhancer of zeste homolog-2(Ezh2),autophagy-related factor LC3A/B(Map1 Lc3b),and p62/sequestosome-1(p62/SQSTM1)-protein.Comparing with controls,Map1 Lc3b,Becn1 and Ezh2 were lower in HCC and RIF-groups(P<0.05).Carm1 was lower in HCC compared to RIF(P<0.05).Hepatic expression of Mmp9 was higher in HCC in relation to the control;the opposite was observed for p62/Sqstm1(P<0.05).Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control(P=0.024).There was no difference among groups for Tuba-1c,Aldolase-B,alpha-fetoprotein,and Mmp2(P>0.05).miR-122 was higher in HCC,and miR-34a in RIF compared to controls(P<0.05).miR-26b was lower in HCC compared to RIF,and the inverse was observed for miR-224(P<0.05).There was no difference among groups regarding miR-33a,miR-143,miR-155,miR-375 and miR-21(P>0.05).CONCLUSION RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.

Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer:Identification,prognosis and survival,genetic and epigenetic factors

Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.

Epigenetic modifications of placenta in women with gestational diabetes mellitus and their offspring

Gestational diabetes mellitus(GDM)is a pregnancy-related complication characterized by abnormal glucose metabolism in pregnant women and has an important impact on fetal development.As a bridge between the mother and the fetus,the placenta has nutrient transport functions,endocrine functions,etc.,and can regulate placental nutrient transport and fetal growth and development according to maternal metabolic status.Only by means of placental transmission can changes in maternal hyperglycemia affect the fetus.There are many reports on the placental pathophysiological changes associated with GDM,the impacts of GDM on the growth and development of offspring,and the prevalence of GDM in offspring after birth.Placental epigenetic changes in GDM are involved in the programming of fetal development and are involved in the pathogenesis of later chronic diseases.This paper summarizes the effects of changes in placental nutrient transport function and hormone secretion levels due to maternal hyperglycemia and hyperinsulinemia on the development of offspring as well as the participation of changes in placental epigenetic modifications due to maternal hyperglycemia in intrauterine fetal programming to promote a comprehensive understanding of the impacts of placental epigenetic modifications on the development of offspring from patients with GDM.

Regulation of TMEM100 expression by epigenetic modification,effects on proliferation and invasion of esophageal squamous carcinoma

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a prevalent malignancy with a high morbidity and mortality rate.TMEM100 has been shown to be suppressor gene in a variety of tumors,but there are no reports on the role of TMEM100 in esophageal cancer(EC).AIM To investigate epigenetic regulation of TMEM100 expression in ESCC and the effect of TMEM100 on ESCC proliferation and invasion.METHODS Firstly,we found the expression of TMEM100 in EC through The Cancer Genome Atlas database.The correlation between TMEM100 gene expression and the survival of patients with EC was further confirmed through Kaplan-Meier analysis.We then added the demethylating agent 5-AZA to ESCC cell lines to explore the regulation of TMEM100 expression by epigenetic modification.To observe the effect of TMEM100 expression on tumor proliferation and invasion by overexpressing TMEM100.Finally,we performed gene set enrichment analysis using the Kyoto Encyclopaedia of Genes and Genomes Orthology-Based Annotation System database to look for pathways that might be affected by TMEM100 and verified the effect of TMEM100 expression on the mitogen-activated protein kinases(MAPK)pathway.RESULTS In the present study,by bioinformatic analysis we found that TMEM100 was lowly expressed in EC patients compared to normal subjects.Kaplan-meier survival analysis showed that low expression of TMEM100 was associated with poor prognosis in patients with EC.Then,we found that the demethylating agent 5-AZA resulted in increased expression of TMEM100 in ESCC cells[quantitative real-time PCR(qRT-PCR)and western blotting].Subsequently,we confirmed that overexpression of TMEM100 leads to its increased expression in ESCC cells(qRT-PCR and western blotting).Overexpression of TMEM100 also inhibited proliferation,invasion and migration of ESCC cells(cell counting kit-8 and clone formation assays).Next,by enrichment analysis,we found that the gene set was significantly enriched in the MAPK signaling pathway.The involvement of TMEM100 in the regulation of MAPK signaling pathway in ESCC cell was subsequently verified by western blotting.CONCLUSION TMEM100 is a suppressor gene in ESCC,and its low expression may lead to aberrant activation of the MAPK pathway.Promoter methylation may play a key role in regulating TMEM100 expression.

The research progress of epigenetics and metabolic memory in diabetic kidney disease

Diabetic kidney disease(DKD)is a clinical syndrome that is one of the major causes of end-stage renal disease(ESRD).The pathogenesis of DKD is complex and multifaceted,with most studies indicating its association with genetics,advanced glycosylation end-product deposition,polyol pathway and protein C activation,lipid metabolism abnormalities,microcirculatory dysfunction,oxidative stress,inflammatory factors,and the kallikrein-kinin system.Epigenetics is the science studying gene expression regulation without changes in the DNA sequence.In recent years,increasing evidence has shown that epigenetic mechanisms play a crucial role in the initiation and progression of DKD.For instance,epigenetic modifications such as DNA methylation,histone modifications,and non-coding RNAs can influence the expression of DKD-related genes,thereby regulating the development and progression of DKD.On the other hand,metabolic memory is an important concept in DKD research.Metabolic memory refers to the phenomenon where cells maintain a certain metabolic state even after the disappearance of metabolic stress factors.This state can influence cell function and fate.In DKD,metabolic stress factors such as hyperglycemia can lead to metabolic memory in renal cells,affecting their function and fate,ultimately leading to the development and progression of DKD.Therefore,to further explore the pathogenesis of DKD,research on epigenetics should be strengthened,aiming to provide new ideas and methods for the prevention and treatment of DKD.

Research Progress on Epigenetic Mechanism of Sarcopenia

In recent years, sarcopenia, as a progressive muscular atrophy and weakness, has become one of the common diseases in the elderly. Although its cause is not fully understood, a growing body of research suggests that epigenetic mechanisms play an important role in the pathogenesis of sarcopenia. The purpose of this review is to summarize the current research progress in the epigenetics of sarcopenia, focusing on the role of DNA methylation, RNA methylation and non-coding RNA in the pathogenesis of sarcopenia. While exploring the epigenetic mechanism of sarcopenia, this study will also look into the application prospect of epigenetics in the treatment strategy of sarcopenia, which will provide new ideas and directions for the treatment of sarcopenia.

Research Progress of Epigenetics in Liver Cancer

Epigenetic changes are changes in gene expression by regulating gene transcription and translation without changing the nucleotide sequence of the genome. Although the genome itself changes during the occurrence and development of most malignant tumors, recent studies have found that epigenetic changes also play an important role in the occurrence and development of tumors. Epigenetic modification mainly includes DNA methylation, histone modification and miRNA regulation. This review focuses on the role and mechanism of epigenetic modification in the occurrence, metastasis and invasion of hepatocellular carcinoma (HCC), and summarizes the latest methods for the treatment of HCC by restoring dysregulated epigenetic modification. It provides a theoretical basis for revealing the pathogenesis of liver cancer and developing new methods of diagnosis and treatment.

Novel insights into histone lysine methyltransferases in cancer therapy:From epigenetic regulation to selective drugs

The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and immune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.

Diet as an epigenetic factor in inflammatory bowel disease

Inflammatory bowel disease(IBD)has as a main characteristic the exacerbation of the immune system against enterocytes,compromising the individual’s intestinal microbiota.This inflammatory cascade causes several nutritional deficiencies,which further compromise immunological functioning and,as a result,worsen the prognosis.This vicious cycle can be interrupted as the patient’s dietary pattern meets their needs according to their clinical condition,acting directly on the inflammatory process of IBD through the interaction of food,intestinal microbiota,and epigenome.Specific nutritional intervention for IBD has a crucial role in preventing and managing disease activity.This review addresses epigenetic modifications through dietary compounds as a mechanism for modulating the intestinal microbiota of patients with IBD.

Epigenetic combined with transcriptomic analysis of the m6A methylome after spared nerve injury-induced neuropathic pain in mice

Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuro pathic pain.N6-methyladenosine(m6A)is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases.However,the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown.In this study,we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve.High-throughput methylated RNA immunoprecipitation sequencing res ults showed that after spared nerve injury,there were 55 m6A methylated and diffe rentially expressed genes in the spinal cord.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury.Over time,the diffe rential gene function at postoperative day 7 was enriched in "positive regulation of neurogenesis" and "positive regulation of neural precursor cell prolife ration." These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance.Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes,such as "very-low-density lipoprotein particle clearance," "negative regulation of choleste rol transport" and "membrane lipid catabolic process." We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling.We speculate that m6A reader enzymes also have an important role in neuropathic pain.These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at diffe rent stages after injury.

Long-noncoding RNAs as epigenetic regulators in neurodegenerative diseases

The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation.Editing the epigenome and epitranscriptome directs the fate of the transcript influencing the functional outcome of each mRNA.In this context,non-coding RNAs play a decisive role in addressing the expression regulation at the gene and chromosomal levels.Long-noncoding RNAs,consisting of more than 200 nucleotides,have been shown to act as epigenetic regulators in several key molecular processes involving neurodegenerative disorders,such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis and Huntington’s disease.Long-noncoding RNAs are abundantly expressed in the central nervous system,suggesting that their deregulation could trigger neuronal degeneration through RNA modifications.The evaluation of their diagnostic significance and therapeutic potential could lead to new treatments for these diseases for which there is no cure.

Mutations in epigenetic regulator KMT2C detected by liquid biopsy are associated with worse survival in prostate cancer patients

Background:KMT2(lysine methyltransferase)family enzymes are epigenetic regulators that activate gene transcription.KMT2C is mainly involved in enhancer-associated H3K4me1,and is also one of the top mutated genes in cancer(6.6%in pan-cancer).Currently,the clinical significance of KMT2C mutations in prostate cancer is understudied.Methods:We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cell-free DNA-based liquid biopsy test results in this study.We investigated the association between KMT2C mutations,other mutations,and pathways.Furthermore,we evaluated the prognostic value of KMT2C mutations,measured by overall survival(OS)and castration resistance-free survival(CRFS).Also,we explored the prognostic value of KMT2C mutations in different patient subgroups.Lastly,we investigated the predictive value of KMT2C mutations in individuals receiving conventional combined anti-androgen blockade(CAB)and abiraterone(ABI)as measured by PSA progression-free survival(PSA-PFS).Results:The KMT2C mutation rate in this cohort is 7.24%(16/221).KMT2C-mutated patients showed worse survival than KMT2C-wild type(WT)patients regarding both CRFS and OS(CRFS:mutated:9.9 vs.WT:22.0 months,p=0.015;OS:mutated:71.9 vs.WT 137.4 months,p=0.012).KMT2C mutations were also an independent risk factor in OS[hazard ratio:3.815(1.461,9.96),p=0.006]in multivariate analyses.Additionally,we explored the association of KMT2C mutations with other genes.This showed that KMT2C mutations were associated with Serine/Threonine-Protein Kinase 11(STK11,p=0.004)and Catenin Beta 1(CTNNB1,p=0.008)mutations.In the CAB treatment,KMT2C-mutated patients had a significantly shorter PSA-PFS compared to KMT2C-WT patients.(PSA-PFS:mutated:9.9 vs.WT:17.6 months,p=0.014).Moreover,KMT2C mutations could effectively predict shorter PSA-PFS in 10 out of 23 subgroups and exhibited a strong trend in the remaining subgroups.Conclusions:KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CRFS and OS,and KMT2C mutations were associated with STK11 and CTNNB1 mutations.Furthermore,KMT2C mutations indicated rapid progression during CAB therapy and could serve as a potential biomarker to predict therapeutic response in prostate cancer.

Influence of methyl donor nutrients as epigenetic regulators in colorectal cancer:A systematic review of observational studies

BACKGROUND Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer(CRC).However,whether the influence of methyl donor intake is modified by polymorphisms in such epigenetic regulators is still unclear.AIM To improve the current understanding of the molecular basis of CRC.METHODS A literature search in the Medline database,Reference Citation Analysis(https://www.referencecitationanalysis.com/),and manual reference screening were performed to identify observational studies published from inception to May 2022.RESULTS A total of fourteen case-control studies and five cohort studies were identified.These studies included information on dietary methyl donors,dietary components that potentially modulate the bioavailability of methyl groups,genetic variants of methyl metabolizing enzymes,and/or markers of CpG island methylator phenotype and/or microsatellite instability,and their possible interactions on CRC risk.CONCLUSION Several studies have suggested interactions between methylenetetrahydrofolate reductase polymorphisms,methyl donor nutrients(such as folate)and alcohol on CRC risk.Moreover,vitamin B6,niacin,and alcohol may affect CRC risk through not only genetic but also epigenetic regulation.Identification of specific mechanisms in these interactions associated with CRC may assist in developing targeted prevention strategies for individuals at the highest risk of developing CRC.

Epigenetic modifications and metabolic memory in diabetic retinopathy:beyond the surface

Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.

Higher rates of autism and attention deficit/hyperactivity disorder in American children:Are food quality issues impacting epigenetic inheritance?

In the United States,schools offer special education services to children who are diagnosed with a learning or neurodevelopmental disorder and have difficulty meeting their learning goals.Pediatricians may play a key role in helping children access special education services.The number of children ages 6-21 in the United States receiving special education services increased 10.4%from 2006 to 2021.Children receiving special education services under the autism category increased 242%during the same period.The demand for special education services for children under the developmental delay and other health impaired categories increased by 184%and 83%respectively.Although student enrollment in American schools has remained stable since 2006,the percentage distribution of children receiving special education services nearly tripled for the autism category and quadrupled for the developmental delay category by 2021.Allowable heavy metal residues remain persistent in the American food supply due to food ingredient manufacturing processes.Numerous clinical trial data indicate heavy metal exposures and poor diet are the primary epigenetic factors responsible for the autism and attention deficit hyperactivity disorder epidemics.Dietary heavy metal exposures,especially inorganic mercury and lead may impact gene behavior across generations.In 2021,the United States Congress found heavy metal residues problematic in the American food supply but took no legislative action.Mandatory health warning labels on select foods may be the only way to reduce dietary heavy metal exposures and improve child learning across generations.

Resveratrol as an epigenetic therapy for flavivirus infection:A narrative review

Flaviviruses are a group of positive-stranded RNA viruses that cause a broad spectrum of severe illnesses in humans worldwide.Clinical manifestations of flavivirus infections range from mild febrile illness to hemorrhage,shock,and neurological manifestations.Flavivirus infections cause a substantial global health impact,with an estimated more than 400 million cases of infections annually.Hence,an understanding of flavivirus-host interaction is urgently needed for new antiviral therapeutic strategies.In recent years,many aspects concerning epigenetic therapy for viral infections have been addressed,including methylation of the genome,acetylation/deacetylation of histone complex and microRNA regulation.In this context,we surveyed and reviewed the literature and summarized the epigenetic effects of resveratrol,a natural polyphenol with potential anti-viral properties,on flavivirus infections.

Comparative DNA-methylome and transcriptome analysis reveals heterosis-and polyploidy-associated epigenetic changes in rice

Heterosis and polyploidy have an overwhelming influence on plant evolution.Recently,polyploid rice hybrids have been used to breed new rice varieties because they combine the advantages of both heterosis and polyploidy.In this study,we generated six rice lines:autotetraploid rice hybrids and their autotetraploid parents,diploid donors,and hybrids of the diploid donors.To investigate the molecular mechanism controlling the effects of both hybridization and polyploidization,we performed bisulfite and RNA sequencing on young panicles at the pollen meiosis stage to compare the DNA metabolomes and transcriptomes among the six rice lines.The hybrids lines were hypermethylated compared to their corresponding parents and the autotetraploid lines showed globally increased DNA methylation of their transposable elements compared to the diploid donors.The alteration in DNA methylation level corresponded to the differential gene expressions among the rice genotypes,suggesting that methylation changes induced by polyploidization and hybridization may affect gene expression.Groups of gene candidates were identified that may be associated with heterosis and polyploidy.Our results provide DNA information that can be used to investigate epigenetic modification during heterosis and polyploidy in rice.

Coordinated transcriptional and post-transcriptional epigenetic regulation during skeletal muscle development and growth in pigs

Background:N6-methyladenosine(m^(6)A)and DNA 5-methylcytosine(5mC)methylation plays crucial roles in diverse biological processes,including skeletal muscle development and growth.Recent studies unveiled a potential link between these two systems,implicating the potential mechanism of coordinated transcriptional and post-transcrip-tional regulation in porcine prenatal myogenesis and postnatal skeletal muscle growth.Methods:Immunofluorescence and co-IP assays were carried out between the 5mC writers and m^(6)A writers to investigate the molecular basis underneath.Large-scale in-house transcriptomic data were compiled for applying weighted correlation network analysis(WGCNA)to identify the co-expression patterns of m^(6)A and 5mC regulators and their potential role in pig myogenesis.Whole-genome bisulfite sequencing(WGBS)and methylated RNA immu-noprecipitation sequencing(MeRIP-seq)were performed on the skeletal muscle samples from Landrace pigs at four postnatal growth stages(days 30,60,120 and 180).Results:Significantly correlated expression between 5mC writers and m^(6)A writers and co-occurrence of 5mC and m^(6)A modification were revealed from public datasets of C2C12 myoblasts.The protein-protein interactions between the DNA methylase and the m^(6)A methylase were observed in mouse myoblast cells.Further,by analyzing tran-scriptome data comprising 81 pig skeletal muscle samples across 27 developmental stages,we identified a 5mC/m^(6)A epigenetic module eigengene and decoded its potential functions in pre-or post-transcriptional regulation in postnatal skeletal muscle development and growth of pigs.Following integrative multi-omics analyses on the WGBS methylome data and MeRIP-seq data for both m^(6)A and gene expression profiles revealed a genome/transcriptome-wide correlated dynamics and co-occurrence of 5mC and m^(6)A modifications as a consequence of 5mC/m^(6)A crosstalk in the postnatal myogenesis progress of pigs.Last,we identified a group of myogenesis-related genes collaboratively regulated by both 5mC and m^(6)A modifications in postnatal skeletal muscle growth in pigs.Conclusions:Our study discloses a potential epigenetic mechanism in skeletal muscle development and provides a novel direction for animal breeding and drug development of related human muscle-related diseases.