Epigenetic Regulatory Mechanisms Research Articles

The epigenetic regulatory mechanisms of ferroptosis and its implications for biological processes and diseases.

Ferroptosis is a form of regulated cell death triggered by the iron-dependent peroxidation of phospholipids. Interactions of iron and lipid metabolism factors jointly promote ferroptosis. Ferroptosis has been demonstrated to be involved in the development of various diseases, such as tumors and degenerative diseases (e.g., aortic dissection), and targeting ferroptosis is expected to be an effective strategy for the treatment of these diseases. Recent studies have shown that the regulation of ferroptosis is affected by multiple mechanisms, including genetics, epigenetics, posttranscriptional modifications, and protein posttranslational modifications. Epigenetic changes have garnered considerable attention due to their importance in regulating biological processes and potential druggability. There have been many studies on the epigenetic regulation of ferroptosis, including histone modifications (e.g., histone acetylation and methylation), DNA methylation, and noncoding RNAs (e.g., miRNAs, circRNAs, and lncRNAs). In this review, we summarize recent advances in research on the epigenetic mechanisms involved in ferroptosis, with a description of RNA N6-methyladenosine (m6A) methylation included, and the importance of epigenetic regulation in biological processes and ferroptosis-related diseases, which provides reference for the clinical application of epigenetic regulators in the treatment of related diseases by targeting ferroptosis.

APOEε4 and risk of Alzheimer's disease - time to move forward.

The inheritance of Apolipoprotein E4 (APOEε4) brings the highest genetic risk of Alzheimer's disease (AD), arguably the highest genetic risk in human pathology. Since the discovery of the association, APOE protein isoforms have been at the center of tens of thousands of studies and reports. While, without a doubt, our knowledge about the normal physiological function of APOE isoforms in the brain has increased tremendously, the questions of how the inheritance of the APOEε4 allele translates into a risk of AD, and the risk is materialized, remain unanswered. Moreover, the knowledge about the risk associated with APOEε4 has not helped design a meaningful preventative or therapeutic strategy. Animal models with targeted replacement of Apoe have been generated and, thanks to the recent NIH/NIA/Alzheimer's disease Association initiative, are now freely available to AD researchers. While helpful in many aspects, none of the available models recapitulates normal physiological transcriptional regulation of the human APOE gene cluster. Changes in epigenetic regulation of APOE alleles in animal models in response to external insults have rarely been if ever, addressed. However, these animal models provide a useful tool to handle questions and investigate protein-protein interactions with proteins expressed by other recently discovered genes and gene variants considered genetic risk factors of AD, like Triggering Receptor expressed on Myeloid cells 2 (TREM2). In this review, we discuss genetic and epigenetic regulatory mechanisms controlling and influencing APOE expression and focus on interactions of APOE and TREM2 in the context of microglia and astrocytes' role in AD-like pathology in animal models.

A fungal microRNA-like RNA regulated effector promotes pathogen infection by targeting a host defense-related transcription factor.

Effectors play important roles in facilitating the infection of plant pathogenic fungi. However, the gene expression regulatory mechanism of effector genes, especially at the post-transcriptional level, is largely unknown. In this study, we uncovered the post-transcriptional regulation of an effector gene VmSP1 by a miRNA-like RNA (Vm-milR16) facilitating the infection of the apple tree Valsa canker pathogen Valsa mali. Genetic and molecular biological assays indicated that the expression of VmSP1 could be suppressed by Vm-milR16-mediated mRNA cleavage in a sequence-specific manner. During V. mali infection, Vm-milR16 was down-regulated, whereas VmSP1 was upregulated, which further indicated the regulation relationship. VmSP1 was further demonstrated to be a secreted protein and could suppress plant immunity. Deletion of VmSP1 did not affect the vegetative growth but significantly reduced the virulence of V. mali. Further study indicated that VmSP1 could interact with the transcription factor MdbHLH189 of apple. Transiently overexpression of MdbHLH189 enhanced host resistance to V. mali by enhancing the expression of apple defense-related genes, together with the increased callose deposition. Silencing of MdbHLH189 compromised host resistance to V. mali. Our findings uncovered the novel epigenetic regulation mechanism of a virulence-associated effector gene mediated by a fungal milRNA at the post-transcriptional level, and the results enriched the understanding of the function and action mechanism of effectors in tree pathogenic fungi.

DNA Methylation-Mediated Mfn2 Gene Regulation in the Brain: A Role in Brain Trauma-Induced Mitochondrial Dysfunction and Memory Deficits.

Repeated mild traumatic brain injuries (rMTBI) affect mitochondrial homeostasis in the brain. However, mechanisms of long-lasting neurobehavioral effects of rMTBI are largely unknown. Mitofusin 2 (Mfn2) is a critical component of tethering complexes in mitochondria-associated membranes (MAMs) and thereby plays a pivotal role in mitochondrial functions. Herein, we investigated the implications of DNA methylation in the Mfn2 gene regulation, and its consequences on mitochondrial dysfunction in the hippocampus after rMTBI. rMTBI dramatically reduced the mitochondrial mass, which was concomitant with decrease in Mfn2 mRNA and protein levels. DNA hypermethylation at the Mfn2 gene promoter was observed post 30days of rMTBI. The treatment of 5-Azacytidine, a pan DNA methyltransferase inhibitor, normalized DNA methylation levels at Mfn2 promoter, which further resulted into restoration of Mfn2 function. The normalization of Mfn2 function was well correlated with recovery in memory deficits in rMTBI-exposed rats. Since, glutamate excitotoxicity serves as a primary insult after TBI, we employed in vitro model of glutamate excitotoxicity in human neuronal cell line SH-SY5Y to investigate the causal epigenetic mechanisms of Mfn2 gene regulation. The glutamate excitotoxicity reduced Mfn2 levels via DNA hypermethylation at Mfn2 promoter. Loss of Mfn2 caused significant surge in cellular and mitochondrial ROS levels with lowered mitochondrial membrane potential in cultured SH-SY5Y cells. Like rMTBI, these consequences of glutamate excitotoxicity were also prevented by 5-AzaC pre-treatment. Therefore, DNA methylation serves as a vital epigenetic mechanism involved in Mfn2 expression in the brain; and this Mfn2 gene regulation may play a pivotal role in rMTBI-induced persistent cognitive deficits. Closed head weight drop injury method was employed to induce repeated mild traumatic brain (rMTBI) in jury in adult, male Wistar rats. rMTBI causes hyper DNA methylation at the Mfn2 promoter and lowers the Mfn2 expression triggering mitochondrial dysfunction. However, the treatment of 5-azacytidine normalizes DNA methylation at the Mfn2 promoter and restores mitochondrial function.

Genome-wide identification of Brassicaceae histone modification genes and their responses to abiotic stresses in allotetraploid rapeseed

BackgroundHistone modification is an important epigenetic regulatory mechanism and essential for stress adaptation in plants. However, systematic analysis of histone modification genes (HMs) in Brassicaceae species is lacking, and their roles in response to abiotic stress have not yet been identified.ResultsIn this study, we identified 102 AtHMs, 280 BnaHMs, 251 BcHMs, 251 BjHMs, 144 BnHMs, 155 BoHMs, 137 BrHMs, 122 CrHMs, and 356 CsHMs in nine Brassicaceae species, respectively. Their chromosomal locations, protein/gene structures, phylogenetic trees, and syntenies were determined. Specific domains were identified in several Brassicaceae HMs, indicating an association with diverse functions. Syntenic analysis showed that the expansion of Brassicaceae HMs may be due to segmental and whole-genome duplications. Nine key BnaHMs in allotetraploid rapeseed may be responsible for ammonium, salt, boron, cadmium, nitrate, and potassium stress based on co-expression network analysis. According to weighted gene co-expression network analysis (WGCNA), 12 BnaHMs were associated with stress adaptation. Among the above genes, BnaPRMT11 simultaneously responded to four different stresses based on differential expression analysis, while BnaSDG46, BnaHDT10, and BnaHDA1 participated in five stresses. BnaSDG46 was also involved in four different stresses based on WGCNA, while BnaSDG10 and BnaJMJ58 were differentially expressed in response to six different stresses. In summary, six candidate genes for stress resistance (BnaPRMT11, BnaSDG46, BnaSDG10, BnaJMJ58, BnaHDT10, and BnaHDA1) were identified.ConclusionsTaken together, these findings help clarify the biological roles of Brassicaceae HMs. The identified candidate genes provide an important reference for the potential development of stress-tolerant oilseed plants.

Molecular mechanisms of cell functioning in norm and pathology

In our study, the following are modern information about the structural and functional organization of cell membranes, the internal apparatus, as well as the cell organelle. The features of the functioning of the structural and dynamic genome are shown, including the main epigenetic mechanisms of gene expression regulation. The cell pathology section describes the main pathological processes that occur in cells after reversible and irreversible damage. The mechanisms and signaling pathways of the phenomenon, markers of cellular aging are highlighted, as well as the significance of this phenomenon in normal and pathological conditions. The main mechanisms of hypoxic and free-radical necrobiosis are described. The mechanisms, signaling pathways, and significance for the norm and pathology of two types of programmed cell death, autophagy and apoptosis, are discussed in detail. The prospect of using fundamental knowledge about the molecular mechanisms of life activity to improve the treatment of the most urgent types of pathology is shown.

Integrated multi-omics analysis identifies epigenetic alteration related to neurodegeneration development in post-traumatic stress disorder patients.

Post-traumatic stress disorder (PTSD), is associated with an elevated risk of neurodegenerative disorders, but the molecular mechanism was not wholly identified. Aberrant methylation status and miRNA expression pattern have been identified to be associated with PTSD, but their complex regulatory networks remain largely unexplored. The purpose of this study was to identify the key genes/pathways related to neurodegenerative disorder development in PTSD by evaluating epigenetic regulatory signature (DNA methylation and miRNA) using an integrative bioinformatic analysis. We integrated DNA expression array data with miRNA and DNA methylation array data - obtained from the GEO database- to evaluate the epigenetic regulatory mechanisms. Our results indicated that target genes of dysregulated miRNAs were significantly related to several neurodegenerative diseases. Several dysregulated genes in the neurodegeneration pathways interacted with some members of the miR-17 and miR-15/107 families. Our analysis indicated that APP/CaN/NFATs signaling pathway was dysregulated in the peripheral blood samples of PTSD. Besides, the DNMT3a and KMT2D genes, as the encoding DNA and histone methyltransferase enzymes, were upregulated, and DNA methylation and miRNA regulators were proposed as critical molecular mechanisms. Our study found dysregulation of circadian rhythm as the CLOCK gene was upregulated and hypomethylated at TSS1500 CpGs S_shores and was also a target of several dysregulated miRNAs. In conclusion, we found evidence of a negative feedback loop between stress oxidative, circadian rhythm dysregulation, miR-17 and miR-15/107 families, some essential genes involved in neuronal and brain cell health, and KMT2D/DNMT3a in the peripheral blood samples of PTSD.

Genome-wide DNA methylation analysis reveals different methylation patterns in Chinese indigenous sheep with different type of tail.

The study was aimed to analyze the difference of genome-wide DNA differential methylation in Lanzhou Large-tailed sheep, Altay sheep and Tibetan sheep, which the typical breeds with different type tails, as to screen the differentially methylated genes (DMGs) that affect the type of tails. In this study, three Lanzhou Large-tailed sheep, three Altay sheep and three Tibetan sheep were detected by whole genome bisulfite sequencing (WGBS). The degree of genome-wide DNA methylation, differentially methylated regions (DMRs) and DMGs were analyzed. The candidate genes affecting the tail type of sheep were identified by GO and KEGG pathway enrichment analysis of DMGs. we identified 68,603 different methylated regions (DMCs) and 75 differentially methylated genes (DMGs) associated with these DMCs. Functional analysis showed that these DMGs were mainly enriched in biological process, cellular component and molecular function, Some of the genes in these pathways are involved in fat metabolism: NFATC4, LPIN2, MGAT2 and MAT2B. Our results may help to further understand the epigenetic regulation mechanisms of deposition of fat in the tail of sheep and provide new basic data for the study of local sheep.

Zip14 ablation modulates HDAC activity through zinc transport in intestinal epithelial cells

Zinc is known for its modulation of proinflammatory responses, in part by targeting nuclear factor kappa B (NF-ĸβ), signal transducer and activator of transcription 3 (STAT3) and expression of specific cytokines, including IFNγ. However, the molecular mechanism underlying Zn-induced cellular response to inflammation remains largely unknown. Our studies, using isolated mouse intestinal epithelial cells (IECs) and mouse intestinal organoids, both derived from Zip14 (Slc39a14) knockout mice, as well as intestinal-specific Zip14 knockout mice, with corresponding control genotypes, were used as models to evaluate the molecular basis for zinc-related inflammatory response in IECs, particularly a potential role for epigenetic modifications. Using chromatin immunoprecipitation (ChIP) assays employing chromatin from IECs, NF-ĸβ was found a major regulator of the Zip14 gene, at steady state. Compared to transcription factors (TFs) STAT3, ATF4 and ATF6, the involvement of NF-ĸβ supports the responsiveness of Zip14 expression with proinflammatory conditions. Similarly, more NF-ĸβ binding was found for iNOS, Cldn-2 and Cldn-8 promoters; all are genes that upregulate in IECs with ablation of Zip14. In contrast, markedly less NF-ĸβ was bound to the promoter of the defense gene IL-18 and C ldn-1; both of which were downregulated with Zip14 ablation. Differential gene expression with Zip14 ablation, as measured by RNA-seq, was limited to ~ 1% of total gene targets, at a false discovery rate of ± 2. RNA from control and Zip14 knockout IECs, intestinal organoids derived from those mice, and an IEC cell line treated with siRNA for Zip14, confirmed the differential expression profiles via qPCR. IECs from the models used here consistently show reduced histone deacetylase (HDAC) activity when Zip14 expression is limited. Moreover, that reduction in activity is concurrent with reduced zinc uptake as measured fluorometrically with the zinc probe, FluoZin-3. Additionally, histone acetylation is greater in IECs when Zip14 is deleted. Treatment of IECs with HDAC inhibitors support a link between Zip14 ablation and HDAC activity. Many HDACs are zinc-metalloenzymes and activity is inhibited with zinc chelation. We propose that deletion of Zip14 lessens HDAC activity, allowing for greater TF occupancy for promoters of specific genes. In summary, we demonstrate that histone acetylation is involved in a zinc-induced anti-inflammatory response in intestinal epithelial cells that is regulated by HDAC activity. Our study shows an important connection between histone modification and the pathological process of zinc-related intestinal inflammation and provides a mechanism for zinc-mediated epigenetic regulation in IECs. Supported by NIH grant DK 094244 and Boston Family Endowment Funds of the University of Florida Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 159: Palmitic Acid Alters Enhancers And Super Enhancers Near Inflammatory And Efferocytosis-associated Genes In Human Monocytes

Background: Elevated free fatty acids (FFA) like palmitic acid (PA) are associated with inflammatory cardiometabolic disorders like diabetes and atherosclerosis. FFA induced dysregulated gene expression in monocytes plays important roles in inflammation, but the epigenetic mechanisms involved are unclear. Here we examined PA induced alterations in enhancer and super-enhancer (E/SE) repertoires to elucidate epigenetic mechanisms of inflammatory gene regulation in monocyte dysfunction. Methods: Human CD14 + monocytes from healthy volunteers were treated with PA (200 μM, 24 h) or vehicle (0.2% BSA). ChIP-seq with histone-H3K27ac was performed to identify Es/SEs and RNA-seq to analyze gene expression genome-wide. Publicly available Genomic Regions Enrichment of Annotations Tool, and datasets from promoter capture Hi-C (PCHiC) and GWAS on diabetes, obesity and BMI were used to analyze functions/disease relevance of Es/SEs. ChIP/RT-qPCRs were used to validate ChIP-/RNA-seq results. Functions of SEs were determined using JQ1 (SE/BET bromodomain inhibitor). Results: ChIP-seq results showed PA extensively dysregulated Es/SEs in CD14 + monocytes vs. vehicle control. PA-regulated Es/SEs showed enrichment of immune system related processes, differentiation, and cytokine production. RNA-seq showed significant correlations between dysregulated enhancers and differential expression of nearby genes. These genes were also altered in adipose tissue macrophages from high fat fed mice, and bone marrow derived macrophages from type2 diabetic db/db mice and Apoe -/- mice with accelerated atherosclerosis. Differentially regulated Es/SEs harbored SNPs associated with diabetes, obesity, and BMI. PCHiC revealed interactions between Es/SEs and promoters of key genes associated with efferocytosis ( MERTK ), metabolism ( OSBPL8 ) and inflammation ( IRAK2, CSF2 and RIPK2 ). Changes in gene expression and H3K27ac at Es/SEs were validated. Treatment with JQ1 reversed PA-induced inflammatory genes in monocytes. Conclusions: PA treatment dysregulated Es/SEs involved in key monocyte functions including efferocytosis, inflammation and metabolism. Targeting such epigenetic mechanisms could be beneficial in the treatment of cardiometabolic diseases.

RNA demethylase ALKBH5 promotes colorectal cancer progression by posttranscriptional activation of RAB5A in an m6A‐YTHDF2‐dependent manner

N6-methyladenosine (m6A) modification is an emerging epigenetic regulatory mechanism in tumourigenesis. Considering that AlkB homolog 5 (ALKBH5) is a well-described m6A demethylase in previous enzyme assays, we aimed to investigate the role of m6A methylation alteration conferred by disturbed ALKBH5 in colorectal cancer (CRC) development. Expression of ALKBH5 and its correlation with clinicopathological characteristics of CRC were evaluated using the prospectively maintained institutional database. The molecular role and underlying mechanism of ALKBH5 in CRC were explored using in vitro and in vivo experiments with methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA-seq, MeRIP-qPCR, RIP-qPCR and luciferase reporter assays. ALKBH5 expression was significantly upregulated in CRC tissues compared to the paired adjacent normal tissues, and higher expression of ALKBH5 was independently associated with worse overall survival in CRC patients. Functionally, ALKBH5 promoted the proliferative, migrative and invasive abilities of CRC cells in vitro and enhanced subcutaneous tumour growth in vivo. Mechanistically, RAB5A was identified as the downstream target of ALKBH5 in CRC development, and ALKBH5 posttranscriptionally activated RAB5A by m6A demethylation, which impeded the YTHDF2-mediated degradation of RAB5A mRNA. In addition, we demonstrated that dysregulation of the ALKBH5-RAB5A axis could affect the tumourigenicity of CRC. ALKBH5 facilitates the progression of CRC by augmenting the expression of RAB5A via an m6A-YTHDF2-dependent manner. Our findings suggested that ALKBH5-RAB5A axis might serve as valuable biomarkers and effective therapeutic targets for CRC.

Inhibition of Histone 3 Lysine 4 Histone Methyltransferase Attenuates DOCA-Salt-Induced Hypertension

Emerging evidence suggests that epigenetic regulatory mechanisms contribute to the development of hypertension. However, whether there is significance of epigenetics on neurogenic hypertension development is not fully understood. We previously reported an elevation of Histone 3 Lysine 4 (H3K4) trimethylation in the paraventricular nucleus of the hypothalamus (PVN). Accordingly, we hypothesize that H3K4 histone methyltransferase (HMT) in the PVN contributes to the development of DOCA-salt hypertension. To test our hypothesis, C57Bl/6J mice were implanted with SHAM or DOCA (50mg) pellets and given free access to water or saline (0.9% NaCl) respectively for 3, 7, or 21 days. H3K4 HMT activity were assessed in the PVN (n = 3-5 mice/group) and expressed as fold change. The HMT activity in the PVN was increased as early as 3 days after DOCA-salt compared with SHAM (6.1 ± 0.69 vs. 1.0 ± 0.73, P < 0.05), remained elevated at day 7 (6.3 ± 1.29 vs. 1.0 ± 0.90, P < 0.05) and day 21 (1.6 ± 0.07 vs. 1.0 ± 0.07, P < 0.05) of DOCA-salt treatment compared with SHAM. To examine the contribution of HMT activity to the development of DOCA-Salt hypertension, another cohort of mice (n = 3-5 mice/group) were implanted with telemetry transmitters to mornitor the blood pressure. After 10 days of recovery, mice treated with DOCA-Salt salt and intracerebroventricularly (ICV) infused with either artificial CSF or 5'-methylthioadenosine (MTA), a H3K4 HMT inhibitor, for 21 days. Importantly, ICV infusion of MTA attenuated mean arterial pressure (123.1 ± 6.3 vs. 138.5 ± 7.4 mmHg, P<0.05) compared with the control following DOCA-salt treatment. In addition, ICV infusion of MTA significantly reduced the H3K4 HMT activity (1.0 ± 0.08 vs 1.7 ± 0.07, P < 0.05) compared with aCSF group following 21 days of DOCA-salt treatment confirming the effectiveness of the inhibitor. In summary, these findings suggest the importance of elevated HMT activity in the PVN in DOCA-salt-induced hypertension. Further studies will be performed to identify the downstream targets of HMT and the mechanisms involved. R01HL122770, 1P20GM130459, R35HL155008-01S1 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Targeting epigenetic modifications in Parkinson's disease therapy.

Parkinson's disease (PD) is a multifactorial disease due to a complex interplay between genetic and epigenetic factors. Recent efforts shed new light on the epigenetic mechanisms involved in regulating pathways related to the development of PD, including DNA methylation, posttranslational modifications of histones, and the presence of microRNA (miRNA or miR). Epigenetic regulators are potential therapeutic targets for neurodegenerative disorders. In the review, we aim to summarize mechanisms of epigenetic regulation in PD, and describe how the DNA methyltransferases, histone deacetylases, and histone acetyltransferases that mediate the key processes of PD are attractive therapeutic targets. We discuss the use of inhibitors and/or activators of these regulators in PD models or patients, and how these small molecule epigenetic modulators elicit neuroprotective effects. Further more, given the importance of miRNAs in PD, their contributions to the underlying mechanisms of PD will be discussed as well, together with miRNA-based therapies.

Epigenetic control is involved in molecular dialogue in plant-microbe symbiosis.

This article is a Commentary on Vigneaud et al. (2023), 238: 2561–2577.

Mutual Regulation of ncRNAs and Chromatin Remodeling Complexes in Normal and Pathological Conditions.

Chromatin remodeling is the one of the main epigenetic mechanisms of gene expression regulation both in normal cells and in pathological conditions. In recent years, a growing number of investigations have confirmed that epigenetic regulators are tightly connected and form a comprehensive network of regulatory pathways and feedback loops. Genes encoding protein subunits of chromatin remodeling complexes are often mutated and change their expression in diseases, as well as non-coding RNAs (ncRNAs). Moreover, different mechanisms of their mutual regulation have already been described. Further understanding of these processes may help apply their clinical potential for establishment of the diagnosis, prognosis, and treatment of the diseases. The therapeutic targeting of the chromatin structure has many limitations because of the complexity of its regulation, with the involvement of a large number of genes, proteins, non-coding transcripts, and other intermediary molecules. However, several successful strategies have been proposed to target subunits of chromatin remodeling complexes and genes encoding them, as well as the ncRNAs that regulate the operation of these complexes and direct them to the target gene regions. In our review, we focus on chromatin remodeling complexes and ncRNAs, their mutual regulation, role in cellular processes and potential clinical application.

Unlocking the Secret to Higher Crop Yield: The Potential for Histone Modifications.

Histone modifications are epigenetic mechanisms, termed relative to genetics, and they refer to the induction of heritable changes without altering the DNA sequence. It is widely known that DNA sequences precisely modulate plant phenotypes to adapt them to the changing environment; however, epigenetic mechanisms also greatly contribute to plant growth and development by altering chromatin status. An increasing number of recent studies have elucidated epigenetic regulations on improving plant growth and adaptation, thus making contributions to the final yield. In this review, we summarize the recent advances of epigenetic regulatory mechanisms underlying crop flowering efficiency, fruit quality, and adaptation to environmental stimuli, especially to abiotic stress, to ensure crop improvement. In particular, we highlight the major discoveries in rice and tomato, which are two of the most globally consumed crops. We also describe and discuss the applications of epigenetic approaches in crop breeding programs.

Histone deacetylase OsHDA706 increases salt tolerance via H4K5/K8 deacetylation of OsPP2C49 in rice.

High salt is a major environmental factor that threatens plant growth and development. Increasing evidence indicates that histone acetylation is involved in plant responses to various abiotic stress; however, the underlying epigenetic regulatory mechanisms remain poorly understood. In this study, we revealed that the histone deacetylase OsHDA706 epigenetically regulates the expression of salt stress response genes in rice (Oryza sativa L.). OsHDA706 localizes to the nucleus and cytoplasm and OsHDA706 expression is significantly induced under salt stress. Moreover, oshda706 mutants showed a higher sensitivity to salt stress than the wild-type. In vivo and in vitro enzymatic activity assays demonstrated that OsHDA706 specifically regulates the deacetylation of lysines 5 and 8 on histone H4 (H4K5 and H4K8). By combining chromatin immunoprecipitation and mRNA sequencing, we identified the clade A protein phosphatase 2 C gene, OsPP2C49, which is involved in the salt response as a direct target of H4K5 and H4K8 acetylation. We found that the expression of OsPP2C49 is induced in the oshda706 mutant under salt stress. Furthermore, the knockout of OsPP2C49 enhances plant tolerance to salt stress, while its overexpression has the opposite effect. Taken together, our results indicate that OsHDA706, a histone H4 deacetylase, participates in the salt stress response by regulating the expression of OsPP2C49 via H4K5 and H4K8 deacetylation.

Cloning of the RNA m6A Methyltransferase 3 and Its Impact on the Proliferation and Differentiation of Quail Myoblasts

Methyltransferase 3 (METTL3), which has been demonstrated to play a crucial role in a variety of biological processes, is the key enzyme for catalyzing m6A modification in RNA. However, the complete protein sequence of METTL3 in quail has not been annotated, and its function in skeletal muscle of quails remains unknown. In the current study, the full-length coding sequence of the quail METTL3 was obtained through the 3' rapid amplification of cDNA ends (3' RACE) and its homology with that of other species was predicted based on a generated phylogenetic tree. A Cell Counting Kit-8 assay and flow cytometry in a quail myoblast cell line (QM7) demonstrated that METTL3 promotes myoblast proliferation. The overexpression of METTL3 in QM7 cells significantly increased the expression levels of the myoblast differentiation markers myogenin (MYOG), myogenic differentiation 1 (MYOD1), and myocyte enhancer factor 2C (MEF2C), further demonstrating that METTL3 promotes myoblast differentiation. Additionally, transcriptome sequencing following METTL3 overexpression revealed that METTL3 controls the expression of various genes involved in RNA splicing and the regulation of gene expression, as well as pathways such as the MAPK signaling pathway. Taken together, our findings demonstrated that METTL3 plays a vital function in quail myoblast proliferation and differentiation and that the METTL3-mediated RNA m6A modification represents an important epigenetic regulatory mechanism in poultry skeletal muscle development.

Notch and Wnt Signaling Modulation to Enhance DPSC Stemness and Therapeutic Potential.

The Dental Pulp of permanent human teeth is home to stem cells with remarkable multilineage differentiation ability: human Dental Pulp Stem Cells (DPSCs). These cells display a very notorious expression of pluripotency core factors, and the ability to give rise to mature cell lineages belonging to the three embryonic layers. For these reasons, several researchers in the field have long considered human DPSCs as pluripotent-like cells. Notably, some signaling pathways such as Notch and Wnt contribute to maintaining the stemness of these cells through a complex network involving metabolic and epigenetic regulatory mechanisms. The use of recombinant proteins and selective pharmacological modulators of Notch and Wnt pathways, together with serum-free media and appropriate scaffolds that allow the maintenance of the non-differentiated state of hDPSC cultures could be an interesting approach to optimize the potency of these stem cells, without a need for genetic modification. In this review, we describe and integrate findings that shed light on the mechanisms responsible for stemness maintenance of hDPSCs, and how these are regulated by Notch/Wnt activation, drawing some interesting parallelisms with pluripotent stem cells. We summarize previous work on the stem cell field that includes interactions between epigenetics, metabolic regulations, and pluripotency core factor expression in hDPSCs and other stem cell types.

Epigenetic Mechanisms of Aging and Aging-Associated Diseases.

Aging is an inevitable outcome of life, characterized by a progressive decline in tissue and organ function. At a molecular level, it is marked by the gradual alterations of biomolecules. Indeed, important changes are observed on the DNA, as well as at a protein level, that are influenced by both genetic and environmental parameters. These molecular changes directly contribute to the development or progression of several human pathologies, including cancer, diabetes, osteoporosis, neurodegenerative disorders and others aging-related diseases. Additionally, they increase the risk of mortality. Therefore, deciphering the hallmarks of aging represents a possibility for identifying potential druggable targets to attenuate the aging process, and then the age-related comorbidities. Given the link between aging, genetic, and epigenetic alterations, and given the reversible nature of epigenetic mechanisms, the precisely understanding of these factors may provide a potential therapeutic approach for age-related decline and disease. In this review, we center on epigenetic regulatory mechanisms and their aging-associated changes, highlighting their inferences in age-associated diseases.