Molecular mechanisms of noncoding RNA and epigenetic regulation in obesity with consequent diabetes mellitus development

Diabetes mellitus(DM)and obesity have become two of the most prevalent and challenging diseases worldwide,with increasing incidence and serious complications.Recent studies have shown that noncoding RNA(ncRNA)and epigenetic regulation play crucial roles in the pathogenesis of DM complicated by obesity.Identification of the involvement of ncRNA and epigenetic regulation in the pathogenesis of diabetes with obesity has opened new avenues of investigation.Targeting these mechanisms with small molecules or RNA-based therapies may provide a more precise and effective approach to diabetes treatment than traditional therapies.In this review,we discuss the molecular mechanisms of ncRNA and epigenetic regulation and their potential therapeutic targets,and the research prospects for DM complicated with obesity.

Epigenetic regulation of dental pulp stem cells and its potential in regenerative endodontics

Regenerative endodontics(RE)therapy means physiologically replacing damaged pulp tissue and regaining functional dentin–pulp complex.Current clinical RE procedures recruit endogenous stem cells from the apical papilla,periodontal tissue,bone marrow and peripheral blood,with or without application of scaffolds and growth factors in the root canal space,resulting in cementum-like and bone-like tissue formation.Without the involvement of dental pulp stem cells(DPSCs),it is unlikely that functional pulp regeneration can be achieved,even though acceptable repair can be acquired.DPSCs,due to their specific odontogenic potential,high proliferation,neurovascular property,and easy accessibility,are considered as the most eligible cell source for dentin–pulp regeneration.The regenerative potential of DPSCs has been demonstrated by recent clinical progress.DPSC transplantation following pulpectomy has successfully reconstructed neurovascularized pulp that simulates the physiological structure of natural pulp.The self-renewal,proliferation,and odontogenic differentiation of DPSCs are under the control of a cascade of transcription factors.Over recent decades,epigenetic modulations implicating histone modifications,DNA methylation,and noncoding(nc)RNAs have manifested as a new layer of gene regulation.These modulations exhibit a profound effect on the cellular activities of DPSCs.In this review,we offer an overview about epigenetic regulation of the fate of DPSCs;in particular,on the proliferation,odontogenic differentiation,angiogenesis,and neurogenesis.We emphasize recent discoveries of epigenetic molecules that can alter DPSC status and promote pulp regeneration through manipulation over epigenetic profiles.

Recent advances in understanding of the epigenetic regulation of plant regeneration

Ever since the concept of"plant cell totipotency"was first proposed in the early twentieth century,plant regeneration has been a major focus of study.Regeneration-mediated organogenesis and genetic transformation are important topics in both basic research and modern agriculture.Recent studies in the model plant Arabidopsis thaliana and other species have expanded our understanding of the molecular regulation of plant regeneration.The hierarchy of transcriptional regulation driven by phytohormone signaling during regeneration is associated with changes in chromatin dynamics and DNA methylation.Here,we summarize how various aspects of epigenetic regulation,including histone modifications and variants,chromatin accessibility dynamics,DNA methylation,and microRNAs,modulate plant regeneration.As the mechanisms of epigenetic regulation are conserved in many plants,research in this field has potential applications in boosting crop breeding,especially if coupled with emerging single-cell omics technologies.

Disease resistance conferred by components of essential chrysanthemum oil and the epigenetic regulation of OsTPS1

The sesquiterpene alpha-bisabolol is the predominant active ingredient in essential oils that are highly valued in the cosmetics industry due to its wound healing,anti-inflammatory,and skin-soothing properties.Alpha-bisabolol was thought to be restricted to Compositae plants.Here we reveal that alpha-bisabolol is also synthesized in rice,a non-Compositae plant,where it acts as a novel sesquiterpene phytoalexin.Overexpressing the gene responsible for the biosynthesis of alpha-bisabolol,Os TPS1,conferred bacterial blight resistance in rice.Phylogenomic analyses revealed that alpha-bisabolol-synthesizing enzymes in rice and Compositae evolved independently.Further experiments demonstrated that the natural variation in the disease resistance level was associated with differential transcription of Os TPS1 due to polymorphisms in its promoter.We demonstrated that Os TPS1 was regulated at the epigenetic level by JMJ705 through the methyl jasmonate pathway.These data reveal the cross-family accumulation and regulatory mechanisms of alpha-bisabolol production.

Epigenetic regulation of N-hydroxypipecolic acid biosynthesis by the AIPP3-PHD2-CPL2 complex

N-Hydroxypipecolic acid(NHP)is a signaling molecule crucial for systemic acquired resistance(SAR),a systemic immune response in plants that provides long-lasting and broad-spectrum protection against secondary pathogen infections.To identify negative regulators of NHP biosynthesis,we performed a forward genetic screen to search for mutants with elevated expression of the NHP biosynthesis gene FLAVIN-DEPENDENT MONOOXYGENASE 1(FMO1).Analysis of two constitutive expression of FMO1(cef)and one induced expression of FMO1(ief)mutants revealed that the AIPP3–PHD2–CPL2 protein complex,which is involved in the recognition of the histone modification H3K27me3 and transcriptional repression,contributes to the negative regulation of FMO1 expression and NHP biosynthesis.Our study suggests that epigenetic regulation plays a crucial role in controlling FMO1 expression and NHP levels in plants.

Epigenetic changes in the regulation of carotenoid metabolism during honeysuckle flower development

Flower development is one of the most vital pathways in plant development, during which the epigenetic regulation of gene expression is essential. DNA methylation, the most conserved epigenetic modification, participates in gene expression regulation and transposable element silencing. Honeysuckle(Lonicera japonica) is an important medicinal plant renowned for its colorful and fragrant flowers. Honeysuckle flowers change color from white to gold as a result of carotenoid accumulation during development. However, the role of DNA methylation in flower color changes is not well understood in L. japonica. Here, we performed whole-genome bisulfite sequencing and transcriptome sequencing during flowering development in honeysuckle. The results showed that a decrease in the levels of genome-wide average DNA methylation during flower development and changes in DNA methylation were associated with the expression of demethylase genes. Moreover, many genes involved in carotenoid biosynthesis and degradation, such as Lj PSY1, LjPDS1, LjLCYE, and LjCCD4, have altered expression levels because of hypomethylation, indicating that DNA methylation plays an important role in flower color changes in honeysuckle. Taken together, our data provide epigenetic insights into flower development and color change in honeysuckles.

Oxidative stress,epigenetic regulation and pathological processes of lens epithelial cells underlying diabetic cataract

Background:Cataract is a blinding disease worldwide.It is an age-related disease that mainly occurs in people over 65 years old.Cataract is also prevalent in patients with diabetes mellites(DM).The pathological mechanisms underlying diabetic cataract(DC)are more complex than that of age-related cataract.Studies have identified that polyol pathway,advanced glycation end products(AGEs)and oxidative stress are the primary pathogenesis of DC.In recent years,molecular-level regulations and pathological processes of lens epithelial cells(LECs)have been confirmed to play roles in the initiation and progression of DC.A comprehensive understanding and elucidation of how chronic hyperglycemia drives molecular-level regulations and cytopathological processes in the lens will shed lights on the prevention,delay and treatment of DC.Main text:Excessive glucose in the lens enhances polyol pathway and AGEs formation.Polyol pathway causes imbalance in the ratio of NADPH/NADPt and NADH/NADt.Decrease in NADPH/NADPt ratio compromises antioxidant enzymes,while increase in NADH/NADt ratio promotes reactive oxygen species(ROS)overproduction in mitochondria,resulting in oxidative stress.Oxidative stress in the lens causes oxidation of DNA,proteins and lipids,leading to abnormalities in their structure and functions.Glycation of proteins by AGEs decreases solubility of proteins.High glucose triggered epigenetic regulations directly or indirectly affect expressions of genes and proteins in LECs.Changes in autophagic activity,increases in fibrosis and apoptosis of LECs destroy the morphological structure and physiological functions of the lens epithelium,disrupting lens homeostasis.Conclusions:In both diabetic animal models and diabetics,oxidative stress plays crucial roles in the formation of cataract.Epigenetic regulations,include lncRNA,circRNA,microRNA,methylation of RNA and DNA,histone acetylation and pathological processes,include autophagy,fibrosis and apoptosis of LECs also involved in DC.

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.

The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis

The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring.

Chromatin and epigenetic regulation of the telomerase reverse transcriptase gene

Telomerase expression and telomere maintenance are critical for long-term cell proliferation and survival,and they play important roles in development,aging,and cancer.Cumulating evidence has indicated that regulation of the rate-limiting subunit of human telomerase reverse transcriptase gene(hTERT)is a complex process in normal cells and many cancer cells.In addition to a number of transcriptional activators and repressors,the chromatin environment and epigenetic status of the endogenous hTERT locus are also pivotal for its regulation in normal human somatic cells and in tumorigenesis.

Genome-wide distribution and functions of the AAE complex in epigenetic regulation in Arabidopsis

Heterochromatin is widespread in eukaryotic genomes and has diverse impacts depending on its genomic context.Previous studies have shown that a protein complex,the ASI1-AIPP1-EDM2(AAE)complex,participates in polyadenylation regulation of several intronic heterochromatin-containing genes.However,the genome-wide functions of AAE are still unknown.Here,we show that the ASI1 and EDM2 mostly target the common genomic regions on a genome-wide level and preferentially interacts with genetic heterochromatin.Polyadenylation(poly(A)sequencing reveals that AAE complex has a substantial influence on poly(A)site usage of heterochromatin-containing genes,includingnotonlyintronicheterochromatincontaining genes but also the genes showing overlap with heterochromatin.Intriguingly,AAE is also involved in the alternative splicing regulation of a number of heterochromatin-overlapping genes,such as the disease resistance gene RPP4.We provided evidence that genic heterochromatin is indispensable for the recruitment of AAE in polyadenylation and splicing regulation.In addition to conferring RNA processing regulation at genic heterochromatin-containing genes,AAE also targets some transposable elements(TEs)outside of genes(including TEs sandwiched by genes and island TEs)for epigenetic silencing.Our results reveal new functions of AAE in RNA processing and epigenetic silencing,and thus representimportantadvancesinepigenetic regulation.

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

B cells play a pivotal role in the pathogenesis of autoimmune diseases.Although previous studies have shown many genetic polymorphisms associated with B-cell activation in patients with various autoimmune disorders,progress in epigenetic research has revealed new mechanisms leading to B-cell hyperactivation.Epigenetic mechanisms,including those involving histone modifications,DNA methylation,and noncoding RNAs,regulate B-cell responses,and their dysregulation can contribute to the pathogenesis of autoimmune diseases.Patients with autoimmune diseases show epigenetic alterations that lead to the initiation and perpetuation of autoimmune inflammation.Moreover,many clinical and animal model studies have shown the promising potential of epigenetic therapies for patients.In this review,we present an up-to-date overview of epigenetic mechanisms with a focus on their roles in regulating functional B-cell subsets.Furthermore,we discuss epigenetic dysregulation in B cells and highlight its contribution to the development of autoimmune diseases.Based on clinical and preclinical evidence,we discuss novel epigenetic biomarkers and therapies for patients with autoimmune disorders.

Metabolic-epigenetic nexus in regulation of stem cell fate

Stem cell fate determination is one of the central questions in stem cell biology,and although its regulation has been studied at genomic and proteomic levels,a variety of biological activities in cells occur at the metabolic level.Metabolomics studies have established the metabolome during stem cell differentiation and have revealed the role of metabolites in stem cell fate determination.While metabolism is considered to play a biological regulatory role as an energy source,recent studies have suggested the nexus between metabolism and epigenetics because several metabolites function as cofactors and substrates in epigenetic mechanisms,including histone modification,DNA methylation,and microRNAs.Additionally,the epigenetic modification is sensitive to the dynamic metabolites and consequently leads to changes in transcription.The nexus between metabolism and epigenetics proposes a novel stem cell-based therapeutic strategy through manipulating metabolites.In the present review,we summarize the possible nexus between metabolic and epigenetic regulation in stem cell fate determination,and discuss the potential preventive and therapeutic strategies via targeting metabolites.

Epigenetic Regulation of Serotonin Transporter in Psychiatric Disorders

SLC6A4 （solute carrier family 6, member 4） gene encodes a serotonin transporter （5-hydroxytryptamine transporter, HTT）, which transports synaptic serotonin into presynaptic terminal. SLC6A4 is known to be the target of antidepressants such as selective serotonin reuptake inhibitors （SSRIs）. Inhibition of HTT increases synaptic serotonin concentration and thereby exerts antidepressant efficacy. A large number of genetic studies suggest the contribution of genetic variations of SLC6A4 to various psychiatric disorders. The most studied genetic variation, HTT-linked polymorphic region （HTTLPR）,

Epigenetic regulation of paired NLR receptors confers durable disease resistance without yield penalty in rice

Subject Code:C14 With the support by the National Natural Science Foundation of China,the research team led by Prof.He Zuhua(何祖华)at the National Key Laboratory of Plant Molecular Genetics and National Center of Plant Gene Research,Shanghai Institute of Plant Physiology&Ecology,Chinese Academy of Sciences,

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.

Efficacy of exercise rehabilitation for managing patients with Alzheimer's disease

Alzheimer's disease(AD) is a progressive and degenerative neurological disease characterized by the deterioration of cognitive functions. While a definitive cure and optimal medication to impede disease progression are currently unavailable, a plethora of studies have highlighted the potential advantages of exercise rehabilitation for managing this condition. Those studies show that exercise rehabilitation can enhance cognitive function and improve the quality of life for individuals affected by AD. Therefore, exercise rehabilitation has been regarded as one of the most important strategies for managing patients with AD. Herein, we provide a comprehensive analysis of the currently available findings on exercise rehabilitation in patients with AD, with a focus on the exercise types which have shown efficacy when implemented alone or combined with other treatment methods, as well as the potential mechanisms underlying these positive effects. Specifically, we explain how exercise may improve the brain microenvironment and neuronal plasticity. In conclusion, exercise is a cost-effective intervention to enhance cognitive performance and improve quality of life in patients with mild to moderate cognitive dysfunction. Therefore, it can potentially become both a physical activity and a tailored intervention. This review may aid the development of more effective and individualized treatment strategies to address the challenges imposed by this debilitating disease, especially in low-and middle-income countries.

How mesenchymal stem cells transform into adipocytes:Overview of the current understanding of adipogenic differentiation

Mesenchymal stem cells(MSCs)are stem/progenitor cells capable of self-renewal and differentiation into osteoblasts,chondrocytes and adipocytes.The transformation of multipotent MSCs to adipocytes mainly involves two subsequent steps from MSCs to preadipocytes and further preadipocytes into adipocytes,in which the process MSCs are precisely controlled to commit to the adipogenic lineage and then mature into adipocytes.Previous studies have shown that the master transcription factors C/enhancer-binding protein alpha and peroxisome proliferation activator receptor gamma play vital roles in adipogenesis.However,the mechanism underlying the adipogenic differentiation of MSCs is not fully understood.Here,the current knowledge of adipogenic differentiation in MSCs is reviewed,focusing on signaling pathways,noncoding RNAs and epigenetic effects on DNA methylation and acetylation during MSC differentiation.Finally,the relationship between maladipogenic differentiation and diseases is briefly discussed.We hope that this review can broaden and deepen our understanding of how MSCs turn into adipocytes.

Epigenetic modification in liver fibrosis:Promising therapeutic direction with significant challenges ahead

Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases.However,current treatment options are limited,highlighting the urgent need for the development of new therapies.As a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver fibrosis.Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still controversial.This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic diseases.The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted.Finally,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed.In summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

Rice melatonin deficiency causes premature leaf senescence via DNA methylation regulation

In a study of DNA methylation changes in melatonin-deficient rice mutants,mutant plants showed premature leaf senescence during grain-filling and reduced grain yield.Melatonin deficiency led to transcriptional reprogramming,especially of genes involved in chlorophyll and carbon metabolism,redox regulation,and transcriptional regulation,during dark-induced leaf senescence.Hypomethylation of mCG and mCHG in the melatonin-deficient rice mutants was associated with the expression change of both protein-coding genes and transposable element-related genes.Changes in gene expression and DNA methylation in the melatonin-deficient mutants were compensated by exogenous application of melatonin.A decreased S-adenosyl-L-methionine level may have contributed to the DNA methylation variations in rice mutants of melatonin deficiency under dark conditions.