Epigenetic Regulatory Mechanisms Research Articles

Research progress on DNMT3A gene expression in Acute myeloid leukemia

DNA methylation is an important epigenetic regulatory mechanism which plays a crucial role in cell differentiation and development. Its function is closely related to DNA methyltransferase 3 alpha (DNMT3A), which can affect gene expression and stem cell differentiation. The mutation rate of the DNMT3A gene is relatively high in Acute myeloid leukemia (AML), but its type and pathogenic mechanism are not yet clear. Further research on DNMT3A may help to identify its pathogenic targets and provide a basis for precise treatment of AML. This article has provided a review for the research progress on the expression of the DNMT3A gene in AML.

DNA hypo-methylation and expression of GBP4 induces T cell exhaustion in pancreatic cancer

Immunotherapy for pancreatic ductal carcinoma (PDAC) remains disappointing due to the repressive tumor microenvironment and T cell exhaustion, in which the roles of interferon-stimulated genes were largely unknown. Here, we focused on a typical interferon-stimulated gene, GBP4, and investigated its potential diagnostic and therapeutic value in pancreatic cancer. Expression analysis on both local samples and public databases indicated that GBP4 was one of the most dominant GBP family members present in the PDAC microenvironment, and the expression level of GBP4 was negatively associated with patient survival. We then identified DNA hypo-methylation in regulatory regions of GBP4 in PDAC, and validated its regulatory role on GBP4 expression via performing targeted methylation using dCas9-SunTag-DNMAT3A-sgRNA-targeted methylation system on selected DNA locus. After that, we investigated the downstream functions of GBP4, and chemotaxis assays indicated that GBP4 overexpression significantly improved the infiltration of CD8+T cells, but also induced upregulation of immune checkpoint genes and T cell exhaustion. Lastly, in vitro T cell killing assays using primary organoids suggested that the PDAC samples with high level of GBP4 expression displayed significantly higher sensitivity to anti-PD-1 treatment. Taken together, our studies revealed the expression patterns and epigenetic regulatory mechanisms of GBP4 in pancreatic cancer and clarified the effects of GBP4 on T cell exhaustion and antitumor immunology.

Epigenetic Regulation and Molecular Mechanisms of Burn Injury-Induced Nociception in the Spinal Cord of Mice

Epigenetic mechanisms, including histone post-translational modifications (PTMs), play a critical role in regulating pain perception and the pathophysiology of burn injury. However, the epigenetic regulation and molecular mechanisms underlying burn injury-induced pain remain insufficiently explored. Spinal dynorphinergic (Pdyn) neurons contribute to heat hyperalgesia induced by severe scalding-type burn injury through p-S10H3-dependent signaling. Beyond p-S10H3, burn injury may impact various other histone H3 PTMs. Double immunofluorescent staining and histone H3 protein analyses demonstrated significant hypermethylation at H3K4me1 and H3K4me3 sites and hyperphosphorylation at S10H3 within the spinal cord. By analyzing Pdyn neurons in the spinal dorsal horn, we found evidence of chromatin activation with a significant elevation in p-S10H3 immunoreactivity. We used RNA-seq analysis to compare the effects of burn injury and formalin-induced inflammatory pain on spinal cord transcriptomic profiles. We identified 98 DEGs for burn injury and 86 DEGs for formalin-induced inflammatory pain. A limited number of shared differentially expressed genes (DEGs) suggest distinct central pain processing mechanisms between burn injury and formalin models. KEGG pathway analysis supported this divergence, with burn injury activating Wnt signaling. This study enhances our understanding of burn injury mechanisms and uncovers converging and diverging pathways in pain models with different origins.

Histone modification in psoriasis: Molecular mechanisms and potential therapeutic targets.

Psoriasis is an immune-mediated, inflammatory disease. Genetic and environmental elements are involved in the nosogenesis of this illness. Epigenetic inheritance serves as the connection between genetic and environmental factors. Histone modification, an epigenetic regulatory mechanism, is implicated in the development of numerous diseases. The basic function of histone modification is to regulate cellular functions by modifying gene expression. Modulation of histone modification, such as regulation of enzymes pertinent to histone modification, can be an alternative approach for treating some diseases, including psoriasis. Herein, we reviewed the regulatory mechanisms and biological effects of histone modifications and their roles in the pathogenesis of psoriasis.

Chidamide Induces Cell Cycle Arrest via NR4A3/P21 Axis Upregulation to Suppress Relapsed and Refractory Acute Myeloid Leukemia

(1) Currently, the survival prognosis for patients with relapsed and refractory acute myeloid leukemia (R/R AML) is extremely poor. Therefore, the exploration of novel drugs is imperative to enhance the prognosis of patients with R/R AML. The therapeutic efficacy and mechanism of Chidamide, a novel epigenetic regulatory drug, in the treatment of R/R AML remain unclear; (2) MethodsThe mechanism of action of Chidamide has been explored in various AML cell lines through various methods such as cell apoptosis, cell cycle analysis, high-throughput transcriptome sequencing, gene silencing, and xenograft models. (3) ResultsHere, we have discovered that chidamide potently induces apoptosis, G0/G1 phase arrest, and mitochondrial membrane potential depolarization in R/R AML cells, encompassing both primary cells and cell lines. Through RNA-seq analysis, we further revealed that chidamide epigenetically regulates the upregulation of differentiation-related pathways while suppressing those associated with cell replication and cell cycle progression. Notably, our screening identified NR4A3 as a key suppressor gene whose upregulation by chidamide leads to P21-dependent cell cycle arrest in the G0/G1 phase. (4) ConclusionsWe have discovered a novel epigenetic regulatory mechanism of chidamide in the treatment of relapsed and refractory acute myeloid leukemia (R/R AML).

Methylation and transcriptome analyses construct a prognostic model and reveal the suppressor role of VMO1 in lung adenocarcinoma

BackgroundDNA methylation is an important epigenetic mechanism of gene regulation. The aberrant DNA methylation has been found to play an important role in the initiation and progression of tumors. ResultsTranscriptome and DNA methylation data of lung adenocarcinoma (LUAD) patients were co-analyzed and 95 methylation-driven genes (MDGs) was found in relation to LUAD. A prognostic model based on 3 MDGs (GMNN, SPINK2 and VMO1) was constructed by Univariate and Multivariate cox regression analyses. The risk score generated from the prognostic model could be used to classify LUAD patients into high and low risk groups. Furthermore, it was found that the risk score was associated with tumor microenvironment (TME) and clinical characteristics (survival status and T stage) of patients. Interestingly, we identified and validated that the patients in the low-risk group responded better to immunotherapy treatment. Then, a nomogram model based on the risk score and clinical characteristics was established which showed significant prediction value. The down-regulation and hypermethylation levels of vitelline membrane outer layer protein 1 homolog (VMO1) were verified in paired LUAD tumor and non-tumor tissues by pyrosequencing assay and RT-qPCR. Furthermore, MTT, migration and wound healing assays were performed with lentivector-mediated ectopic over-expression and 5-Aza-dC demethylation followed by siRNA rescue experiments to investigate the role of VMO1 in LUAD cells. Our results indicated that VMO1 could inhibit proliferation and migration of A549 and NCI-H1299 cells. ConclusionsIn summary, our experiments constructed a prognostic model with high capacity for risk prediction in LUAD patients. VMO1 had a malignant suppressor role in LUAD cells. The correlation between risk score and TME might elucidate a potential mechanism of oncogenesis and provide an avenue for further therapeutic targets.

Transcriptome-Wide Identification of m6A Writers, Erasers and Readers and Their Expression Profiles under Various Biotic and Abiotic Stresses in Pinus massoniana Lamb.

N6-methyladenosine (m6A) RNA modification is the most prevalent form of RNA methylation and plays a crucial role in plant development. However, our understanding of m6A modification in Masson pine (Pinus massoniana Lamb.) remains limited. In this study, a complete analysis of m6A writers, erasers, and readers in Masson pine was performed, and 22 m6A regulatory genes were identified in total, including 7 m6A writers, 7 m6A erases, and 8 readers. Phylogenetic analysis revealed that all m6A regulators involved in Masson pine could be classified into three distinct groups based on their domains and motifs. The tissue expression analysis revealed that the m6A regulatory gene may exert a significant influence on the development of reproductive organs and leaves in Masson pine. Moreover, the results from stress and hormone expression analysis indicated that the m6A regulatory gene in Masson pine might be involved in drought stress response, ABA-signaling-pathway activation, as well as resistance to Monochamus alternatus. This study provided valuable and anticipated insights into the regulatory genes of m6A modification and their potential epigenetic regulatory mechanisms in Masson pine.

Targeting DNA Methylation Machinery in Pediatric Solid Tumors.

DNA methylation is a key epigenetic regulatory mechanism that plays a critical role in a variety of cellular processes, including the regulation of cell fate during development, maintenance of cell identity, and genome stability. DNA methylation is tightly regulated by enzymatic reactions and its deregulation plays an important role in the development of cancer. Specific DNA methylation alterations have been found in pediatric solid tumors, providing new insights into the development of these tumors. In addition, DNA methylation profiles have greatly contributed to tune the diagnosis of pediatric solid tumors and to define subgroups of patients with different risks of progression, leading to the reduction in unwanted toxicity and the improvement of treatment efficacy. This review highlights the dysregulated DNA methylome in pediatric solid tumors and how this information provides promising targets for epigenetic therapies, particularly inhibitors of DNMT enzymes (DNMTis). Opportunities and limitations are considered, including the ability of DNMTis to induce viral mimicry and immune signaling by tumors. Besides intrinsic action against cancer cells, DNMTis have the potential to sensitize immune-cold tumors to immunotherapies and may represent a remarkable option to improve the treatment of challenging pediatric solid tumors.

Plant responses to abiotic stress regulated by histone acetylation.

In eukaryotes, histone acetylation and deacetylation play an important role in the regulation of gene expression. Histone acetylation levels are reversibly regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Increasing evidence highlights histone acetylation plays essential roles in the regulation of gene expression in plant response to environmental stress. In this review, we discussed the recent advance of histone acetylation in the regulation of abiotic stress responses including temperature, light, salt and drought stress. This information will contribute to our understanding of how plants adapt to environmental changes. As the mechanisms of epigenetic regulation are conserved in many plants, research in this field has potential applications in improvement of agricultural productivity.

Epigenetic insights into an epimutant colorless non-ripening: from fruit ripening to stress responses.

The epigenetic machinery has received extensive attention due to its involvement in plant growth, development, and adaptation to environmental changes. Recent studies often highlight the epigenetic regulatory network by discussing various epigenetic mutants across various plant species. However, a systemic understanding of essential epigenetic regulatory mechanisms remains limited due to a lack of representative mutants involved in multiple biological processes. Colorless Non-ripening (Cnr), a spontaneous epimutant isolated from a commercial population, was initially characterized for its role in fruit ripening regulation. Cnr fruits exhibit an immature phenotype with yellow skin, attributed to hypermethylation of the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE-CNR (SlSPL-CNR) promoter, resulting in the repression of gene expression. In addition to DNA methylation, this process also involves histone modification and microRNA, integrating multiple epigenetic regulatory factors. Interestingly, knockout mutants of SlSPL-CNR display phenotypical distinctions from Cnr in fruit ripening, indicating complex genetic and epigenetic control over the non-ripening phenotype in Cnr fruits. Accumulating evidence suggests that Cnr epimutation is pleiotropic, participating in various biological processes such as Cd stress, Fe deficiency, vivipary, and cell death. Therefore, the Cnr epimutant serve as an excellent model for unveiling how epigenetic mechanisms are involved in diverse biological processes. This review paper focuses on recent research advances regarding the Cnr epimutant, delving into its complex genetic and epigenetic regulatory mechanisms, with the aim of enhancing our understanding and facilitating the development of high-quality, high-yield crops through epigenetic modification.

Methyl-Sensitive Amplification Polymorphism (MSAP) Analysis Provides Insights into the DNA Methylation Changes Underlying Adaptation to Low Temperature of Brassica rapa L.

DNA methylation can change rapidly to regulate the expression of stress-responsive genes. Previous studies have shown that there are significant differences in the cold resistance of winter rapeseed (Brassica rapa L.) after being domesticated in different selection environments; however, little is known about the epigenetic regulatory mechanisms of its cold resistance formation. Four winter rapeseed materials ('CT-2360', 'MXW-1', '2018-FJT', and 'DT-7') domesticated in different environments were selected to analyze the DNA methylation level and pattern changes under low temperature using methylation-sensitive amplified polymorphism technology with 60 primer pairs. A total of 18 pairs of primers with good polymorphism were screened, and 1426 clear bands were amplified, with 594 methylation sites, accounting for 41.65% of the total amplified bands. The total methylation ratios of the four materials were reduced after low-temperature treatment, in which the DNA methylation level of 'CT-2360' was higher than that of the other three materials; the analysis of methylation patterns revealed that the degree of demethylation was higher than that of methylation in 'MXW-1', '2018-FJT', and 'DT-7', which were 22.99%, 19.77%, and 24.35%, respectively, and that the methylation events in 'CT-2360' were predominantly dominant at 22.95%. Fifty-three polymorphic methylated DNA fragments were randomly selected and further analyzed, and twenty-nine of the cloned fragments were homologous to genes with known functions. The candidate genes VQ22 and LOC103871127 verified the existence of different expressive patterns before and after low-temperature treatment. Our work implies the critical role of DNA methylation in the formation of cold resistance in winter rapeseed. These results provide a comprehensive insight into the adaptation epigenetic regulatory mechanism of Brassica rapa L. to low temperature, and the identified differentially methylated genes can also be used as important genetic resources for the multilateral breeding of winter-resistant varieties.

Targeted Treatment of Acute Myeloid Leukemia Based on Epigenetic Regulation Mechanism

Targeted Treatment of Acute Myeloid Leukemia Based on Epigenetic Regulation Mechanism

Inflammasomes Are Influenced by Epigenetic and Autophagy Mechanisms in Colorectal Cancer Signaling.

Inflammasomes contribute to colorectal cancer signaling by primarily inducing inflammation in the surrounding tumor microenvironment. Its role in inflammation is receiving increasing attention, as inflammation has a protumor effect in addition to inducing tissue damage. The inflammasome's function is complex and controlled by several layers of regulation. Epigenetic processes impact the functioning or manifestation of genes that are involved in the control of inflammasomes or the subsequent signaling cascades. Researchers have intensively studied the significance of epigenetic mechanisms in regulation, as they encompass several potential therapeutic targets. The regulatory interactions between the inflammasome and autophagy are intricate, exhibiting both advantageous and harmful consequences. The regulatory aspects between the two entities also encompass several therapeutic targets. The relationship between the activation of the inflammasome, autophagy, and epigenetic alterations in CRC is complex and involves several interrelated pathways. This article provides a brief summary of the newest studies on how epigenetics and autophagy control the inflammasome, with a special focus on their role in colorectal cancer. Based on the latest findings, we also provide an overview of the latest therapeutic ideas for this complex network.

Whole-genome DNA methylation profiling revealed epigenetic regulation of NF-κB signaling pathway involved in response to Vibrio alginolyticus infection in the Pacific oyster, Crassostrea gigas

DNA methylation, an essential epigenetic alteration, is tightly linked to a variety of biological processes, such as immune response. To identify the epigenetic regulatory mechanism in Pacific oyster (Crassostrea gigas), whole-genome bisulfite sequencing (WGBS) was conducted on C. gigas at 0 h, 6 h, and 48 h after infection with Vibrio alginolyticus. At 6 h and 48 h, a total of 11,502 and 14,196 differentially methylated regions (DMRs) were identified (p<0.05, FDR<0.001) compared to 0 h, respectively. Gene ontology (GO) analysis showed that differentially methylated genes (DMGs) were significantly enriched in various biological pathways including immunity, cytoskeleton, epigenetic modification, and metabolic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that transcription machinery (ko03021) is one of the most important pathways. Integrated transcriptome and methylome analyses allowed the identification of 167 and 379 DMG-related DEGs at 6 h and 48 h, respectively. These genes were significantly enriched in immune-related pathways, including nuclear factor kappa B (NF-κB) signaling pathway (ko04064) and tumor necrosis factor (TNF) signaling pathway (ko04668). Interestingly, it's observed that the NF-κB pathway could be activated jointly by TNF Receptor Associated Factor 2 (TRAF2) and Baculoviral IAP Repeat Containing 3 (BIRC3, the homolog of human BIRC2) which were regulated by DNA methylation in response to the challenge posed by V. alginolyticus infection. Through this study, we provided insightful information about the epigenetic regulation of immunity-related genes in the C. gigas, which will be valuable for the understanding of the innate immune system modulation and defense mechanism against bacterial infection in invertebrates.

Oxidative Stress in Breast Cancer: A Biochemical Map of Reactive Oxygen Species Production.

This review systematizes information about the metabolic features of breast cancer directly related to oxidative stress. It has been shown those redox changes occur at all levels and affect many regulatory systems in the human body. The features of the biochemical processes occurring in breast cancer are described, ranging from nonspecific, at first glance, and strictly biochemical to hormone-induced reactions, genetic and epigenetic regulation, which allows for a broader and deeper understanding of the principles of oncogenesis, as well as maintaining the viability of cancer cells in the mammary gland. Specific pathways of the activation of oxidative stress have been studied as a response to the overproduction of stress hormones and estrogens, and specific ways to reduce its negative impact have been described. The diversity of participants that trigger redox reactions from different sides is considered more fully: glycolytic activity in breast cancer, and the nature of consumption of amino acids and metals. The role of metals in oxidative stress is discussed in detail. They can act as both co-factors and direct participants in oxidative stress, since they are either a trigger mechanism for lipid peroxidation or capable of activating signaling pathways that affect tumorigenesis. Special attention has been paid to the genetic and epigenetic regulation of breast tumors. A complex cascade of mechanisms of epigenetic regulation is explained, which made it possible to reconsider the existing opinion about the triggers and pathways for launching the oncological process, the survival of cancer cells and their ability to localize.

The single-cell chromatin landscape in gonadal cell lineage specification

Gonad development includes sex determination and divergent maturation of the testes and ovaries. Recent advances in measuring gene expression in single cells are providing new insights into this complex process. However, the underlying epigenetic regulatory mechanisms remain unclear. Here, we profiled chromatin accessibility in mouse gonadal cells of both sexes from embryonic day 11.5 to 14.5 using single-cell assay for transposase accessible chromatin by sequencing (scATAC-seq). Our results showed that individual cell types can be inferred by the chromatin landscape, and that cells can be temporally ordered along developmental trajectories. Integrative analysis of transcriptomic and chromatin-accessibility maps identified multiple putative regulatory elements proximal to key gonadal genes Nr5a1, Sox9 and Wt1. We also uncover cell type-specific regulatory factors underlying cell type specification. Overall, our results provide a better understanding of the epigenetic landscape associated with the progressive restriction of cell fates in the gonad.

The role and therapeutic potential of macrophages in the pathogenesis of diabetic cardiomyopathy.

This review provides a comprehensive analysis of the critical role played by macrophages and their underlying mechanisms in the progression of diabetic cardiomyopathy (DCM). It begins by discussing the origins and diverse subtypes of macrophages, elucidating their spatial distribution and modes of intercellular communication, thereby emphasizing their significance in the pathogenesis of DCM. The review then delves into the intricate relationship between macrophages and the onset of DCM, particularly focusing on the epigenetic regulatory mechanisms employed by macrophages in the context of DCM condition. Additionally, the review discusses various therapeutic strategies aimed at targeting macrophages to manage DCM. It specifically highlights the potential of natural food components in alleviating diabetic microvascular complications and examines the modulatory effects of existing hypoglycemic drugs on macrophage activity. These findings, summarized in this review, not only provide fresh insights into the role of macrophages in diabetic microvascular complications but also offer valuable guidance for future therapeutic research and interventions in this field.

Prenatal nicotine exposure leads to epigenetic alterations in peripheral nervous system signaling genes in the testis of the rat

BackgroundPrenatal nicotine exposure (PNE) has been documented to cause numerous deleterious effects on fetal development. However, the epigenetic changes promoted by nicotine exposure on germ cells are still not well understood.ObjectivesIn this study, we focused on elucidating the impact of prenatal nicotine exposure on regulatory epigenetic mechanisms important for germ cell development.MethodsSprague-Dawley rats were exposed to nicotine during pregnancy and male progeny was analyzed at 11 weeks of age. Testis morphology was analyzed using frozen testis sections and expression of germ cell markers was examined by RT-qPCR; histone modifications were assessed by Western Blot (WB). DNA methylation analysis was performed by methylation-specific PCR of bisulfite converted DNA. Genome-wide DNA methylation was analyzed using Methylated DNA immunoprecipitation (MeDIP)-seq. We also carried out transcriptomics analysis of pituitary glands by RNA-seq.ResultsWe show that gestational exposure to nicotine reduces germ cell numbers, perturbs meiosis, affects the expression of germ line reprogramming responsive genes, and impacts the DNA methylation of nervous system genes in the testis. PNE also causes perturbation of gene expression in the pituitary gland of the brain.ConclusionsOur data demonstrate that PNE leads to perturbation of male spermatogenesis, and the observed effects are associated with changes of peripheral nervous system signaling pathways. Alterations in the expression of genes associated with diverse biological activities such as cell migration, cell adhesion and GABA signaling in the pituitary gland underscore the complexity of the effects of nicotine exposure during pregnancy.

EPB41L4A-AS1 is required to maintain basal autophagy to modulates Aβ clearance

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques. Aβ is generated from the cleavage of the amyloid precursor protein by β and γ-secretases and cleared by neuroglial cells mediated autophagy. The imbalance of the intracellular Aβ generation and clearance is the causative factor for AD pathogenesis. However, the exact underlying molecular mechanisms remain unclear. Our previous study reported that EPB41L4A-AS1 is an aging-related long non-coding RNA (lncRNA) that is repressed in patients with AD. In this study, we found that downregulated EPB41L4A-AS1 in AD inhibited neuroglial cells mediated-Aβ clearance by decreasing the expression levels of multiple autophagy-related genes. We found that EPB41L4A-AS1 regulates the expression of general control of amino acid synthesis 5-like 2, an important histone acetyltransferase, thus affecting histone acetylation, crotonylation, and lactylation near the transcription start site of autophagy-related genes, ultimately influencing their transcription. Collectively, this study reveals EPB41L4A-AS1 as an AD-related lncRNA via mediating Aβ clearance and provides insights into the epigenetic regulatory mechanism of EPB41L4A-AS1 in gene expression and AD pathogenesis.

H3K27me3 timely dictates uterine epithelial transcriptome remodeling and thus transformation essential for normal embryo implantation.

Uterine luminal epithelia (LE), the first layer contacting with the blastocyst, acquire receptivity for normal embryo implantation. Besides the well-accepted transcriptional regulation dominated by ovarian estrogen and progesterone for receptivity establishment, the involvement of epigenetic mechanisms remains elusive. This study systematically profiles the transcriptome and genome-wide H3K27me3 distribution in the LE throughout the preimplantation. Combining genetic and pharmacological approaches targeting the PRC2 core enzyme Ezh1/2, we demonstrate that the defective remodeling of H3K27me3 in the preimplantation stage disrupts the differentiation of LE, and derails uterine receptivity, resulting in implantation failure. Specifically, crucial epithelial genes, Pgr, Gata2, and Sgk1, are transcriptionally silenced through de novo deposition of H3K27me3 for LE transformation, and their sustained expression in the absence of H3K27me3 synergistically confines the nuclear translocation of FOXO1. Further functional studies identify several actin-associated genes, including Arpin, Tmod1, and Pdlim2, as novel direct targets of H3K27me3. Their aberrantly elevated expression impedes the morphological remodeling of LE, a hindrance alleviated by treatment with cytochalasin D which depolymerizes F-actin. Collectively, this study uncovers a previously unappreciated epigenetic regulatory mechanism for the transcriptional silencing of key LE genes via H3K27me3, essential for LE differentiation and thus embryo implantation.