Epigenetic Regulatory Mechanisms Research Articles

The methyltransferase MLL4 promotes non-alcoholic steatohepatitis by enhancing NF-κB signaling.

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem worldwide, ranging from non-alcoholic fatty liver (NAFL) to the more severe metabolic non-alcoholic steatohepatitis (NASH). Although many studies have elucidated the pathogenesis of NAFLD, the epigenetic regulatory mechanism from NAFL to NASH remains incompletely understood. The histone H3 lysine 4 methyltransferase, MLL4 (also called KMT2D), is a critical epigenetic transcriptional coactivator that mediates overnutrition-induced steatosis in mice, but its potential role in the progression of NASH remains largely unknown. Here, we show that mice lacking the one allele of the Mll4 gene are resistant to hepatic steatosis, inflammation, and fibrosis in NASH conditions compared to wild-type controls. Transcriptome analysis of the livers of control and Mll4+/- mice identified pro-inflammatory genes regulated by the nuclear factor kappa B (NF-κB) signaling pathway as major target genes of MLL4. We show that MLL4 binds to p65 and that MLL4 is required for NF-κB transactivation. Myeloid-specific Mll4 knockout mice showed an almost complete block of NASH, while hepatocyte-specific Mll4 knockout mice showed mild inhibition of steatosis. Pro-inflammatory M1 polarization is decreased and anti-inflammatory M2 polarization is increased in liver macrophages from myeloid-specific Mll4 knockout mice. Importantly, we show that histone H3-lysine 4 methylation mediated by the MLL4-complex plays a critical role in promoting the expression of Ccl2 in hepatocytes and M1 marker genes in macrophages. Our results demonstrate that MLL4, through the NF-κB-MLL4 regulatory axis, exacerbates steatohepatitis in the context of an inflammatory response and represents a potential therapeutic target for NASH.

Binding of PtoRAP2.12 to demethylated and accessible chromatin regions in the PtoGntK promoter stimulates growth of poplar.

DNA methylation is an essential epigenetic modification for gene regulation in plant growth and development. However, the precise mechanisms of DNA methylation remain poorly understood, especially in woody plants. We employed whole-genome bisulfite sequencing (WGBS), assays for transposase-accessible chromatin using sequencing (ATAC-seq), and RNA-Seq to investigate epigenetic regulatory relationships in Populus tomentosa treated with DNA methylation inhibitor 5-azacitidine. Expression-quantitative trait methylation analysis (eQTM), epigenome-wide association study (EWAS), and joint linkage-linkage disequilibrium mapping were used to explore the epigenetic regulatory genes, and using CRISPR/Cas9 to identify the role of candidate genes. Plant developmental abnormalities occurred when DNA methylation levels were substantially reduced. DNA methylation regulated 112 expressed genes via chromatin accessibility, of which 61 genes were significantly influenced by DNA methylation variation at the population level. One DNA methylation-regulated gene, PtoGntK, was located in a major quantitative trait locus (QTL) for poplar growth. Overexpression and CRISPR/Cas9 of PtoGntK revealed it affected poplar height and stem diameter. The PtoRAP2.12 was found to bind to the demethylated accessible region in the PtoGntK promoter, thereby promoting growth in poplar. This study identified key genes with epigenetic regulation for plant growth and provides insights into epigenetic regulation mechanisms in woody plants.

SMYD family in cancer: epigenetic regulation and molecular mechanisms of cancer proliferation, metastasis, and drug resistance.

Epigenetic modifiers (miRNAs, histone methyltransferases (HMTs)/demethylases, and DNA methyltransferases/demethylases) are associated with cancer proliferation, metastasis, angiogenesis, and drug resistance. Among these modifiers, HMTs are frequently overexpressed in various cancers, and recent studies have increasingly identified these proteins as potential therapeutic targets. In this review, we discuss members of the SET and MYND domain-containing protein (SMYD) family that are topics of extensive research on the histone methylation and nonhistone methylation of cancer-related genes. Various members of the SMYD family play significant roles in cancer proliferation, metastasis, and drug resistance by regulating cancer-specific histone methylation and nonhistone methylation. Thus, the development of specific inhibitors that target SMYD family members may lead to the development of cancer treatments, and combination therapy with various anticancer therapeutic agents may increase treatment efficacy.

Deciphering Mechanisms of Adipocyte Differentiation in Abdominal Fat of Broilers.

The excessive deposition of abdominal fat tissue (AFT) in broilers has emerged as a major concern in the poultry industry. Despite some progress in recent years, the molecular mechanisms underlying AFT development remain ambiguous. The current study combined RNA-seq with transposase-accessible chromatin sequencing (ATAC-seq) to map the dynamic profiling of chromatin accessibility and transcriptional reprogramming in AFT adipocyte differentiation in broilers at day 3 (D3) and D14. Our results found that the levels of CDK1 and PCNA were down-regulated at D14, D28, and D42 compared to D3, while the levels of C/EBPα and FABP4 were up-regulated at D14 and D42 compared to D3. Meanwhile, PPARγ was significantly up-regulated at D28 and D42. RNA-seq of AFT identified 1705 up-regulated and 1112 down-regulated differential expression genes (DEGs) between D3 and D14. Pathways based on up-regulated DEGs mainly enriched some pathways related to adipocyte differentiation, while down-regulated DEGs pointed to DNA replication, cell cycle, and gap junction. Gene set enrichment analysis (GSEA) revealed that DNA replication and the cell cycle were down-regulated at D14, while the insulin signaling pathway was up-regulated. In the OA-induced immortalized chicken preadipocyte (ICP2) model, protein dynamic changes were consistent with AFT from D3 to D14. Same pathways were enriched in ICP2. In addition, based on overlapped DEGs from AFT and ICP2, enriched pathways related to adipocyte differentiation or proliferation mentioned above were all involved. A total of 1600 gain and 16727 loss differential peaks (DPs) were identified in ICP2 by ATAC-seq. Predicted genes from DPs at the promoter regions were enriched in glycerophospholipid metabolism, TGF-β signaling, FoxO signaling, and ubiquitin-mediated proteolysis. DNA motifs predicted 159 transcription factors (TFs) based on gain and loss peaks from the promoter regions, where 1 and 10 TFs were overlapped with up or down TFs from DEGs. Overall, this study presents a framework for the comprehension of the epigenetic regulatory mechanisms of adipocyte differentiation and identifies candidate genes and potential TFs involved in AFT adipocyte differentiation in broilers.

Integrated mRNA-seq and miRNA-seq analysis reveals key transcription factors of HNF4α and KLF4 in ADPKD

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic disorder affecting the kidneys. Understanding epigenetic regulatory mechanisms and the role of microRNAs (miRNAs) is crucial for developing therapeutic interventions. Two mRNA datasets (GSE7869 and GSE35831) and miRNA expression data (GSE133530) from ADPKD patients were used to find differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs), with a focus on genes regulated by hub transcription factors (TFs) and their target genes. The expression of hub TFs was validated in human kidneys and animal models through Western Blot (WB) and RT-PCR analysis. The location of the hub TF proteins in kidney cells was observed by a laser confocal microscope. A total of 2037 DEGs were identified. DEM analysis resulted in 59 up-regulated and 107 down-regulated miRNAs. Predicted target DEGs of DEMs indicated two top dysregulated TFs: hepatocyte nuclear factor 4 alpha (HNF4α) and Kruppel-like factor 4 (KLF4). RT-PCR, WB, and immunochemistry results showed that mRNA and protein levels of HNF4α were significantly decreased while KLF4 levels were significantly up-regulated in human ADPKD kidneys and Pkd1 conditional knockout mice compared with normal controls. Laser confocal microscopy revealed that KLF4 was mainly located in the cytoplasm while HNF4α was in the nucleus. Functional enrichment analysis indicated that genes regulated by HNF4α were mainly associated with metabolic pathways, while KLF4-regulated genes were linked to kidney development. Drug response prediction analysis revealed potential drug candidates for ADPKD treatment, including BI-2536, Sepantronium, and AZD5582. This integrated analysis provides new epigenetic insights into the complex miRNA-TF-mRNA network in ADPKD and identifies HNF4α and KLF4 as key TFs. These findings offer valuable resources for further research and potential drug development for ADPKD.

Epigenetic Regulation of CXC Chemokine Expression by Environmental Electrophiles Through DNA Methyltransferase Inhibition.

Ubiquitously distributed environmental electrophiles covalently modify DNA and proteins, potentially leading to adverse health effects. However, the impacts of specific electrophiles on target proteins and their physiological roles remain largely unknown. In the present study, we focused on DNA methylation, which regulates gene expression and physiological responses. A total of 45 environmental electrophiles were screened for inhibitory effects on the activity of DNA methyltransferase 3B (DNMT3B), a key enzyme in DNA methylation, and four compounds were identified. We focused on 1,2-naphthoquinone (1,2-NQ), an air pollutant whose toxicity has been reported previously. Interestingly, we found that 1,2-NQ modified multiple lysine and histidine residues in DNMT3B, one of which was near the active site in DNMT3B. It was found that 1,2-NQ altered gene expression and evoked inflammatory responses in lung adenocarcinoma cell lines. Furthermore, we found that 1,2-NQ upregulated CXCL8 expression through DNA demethylation of the distal enhancer and promoted cancer cell growth. Our study reveals novel mechanisms of epigenetic regulation by environmental electrophiles through the inhibition of DNMT3B activity and suggests their physiological impact.

Higher risk of recurrence in early-stage breast cancer patients with increased levels of ribosomal protein S6

PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer.

Insights into the DNA methylation of Portunus trituberculatus in response to Vibrio parahaemolyticus infection

Vibrio parahaemolyticus is the main pathogen causing acute hepatopancreatic necrotic disease in crustaceans. To elucidate the epigenetic regulatory mechanism of crustacean resistance to V. parahaemolyticus infection, we conducted artificial infection studies on Portunus trituberculatus. The results showed that the mortality rate reached the highest at 12 h of artificial infection, which was 23.69 %. At 72 h after V parahaemolyticus infection, the expression level of DNA demethylase (ten-eleven-translocation protein) Tet was significantly decreased, the expression of DNA methyltransferase Dnmt3B fluctuated significantly. Based on the differential expression levels of Tet and Dnmt3B. We depict for DNA methylation profiles of the whole genome of P. trituberculatus at single-base resolution by using whole-genome bisulfite sequencing (WGBS) on hemolymph tissues. The overall DNA methylation level was low at 2.16% in P. trituberculatus hemolymph. A total of 2,590 differentially methylated regions (DMRs) were identified, of which 1,329 were hypermethylated and 1,261 were hypomethylated, and 1,389 genes were annotated in these DMRs. Differently methylated genes (DMGs) were significantly enriched in ribosomes (KO03010), protein kinases (KO01001), cell cycle (HSA04110), endocrine resistance (HSA01522) and FoxO signaling pathway (KO04068). Finally, we selected six differentially methylated genes for quantitative analysis. The results showed that DNA methylation not only has a negative regulatory effect on gene expression, but also has a positive regulatory effect. These results indicated that DNA methylation in the regulation of genes involved in immune responses contributes to the resistance of P. trituberculatus to V. parahaemolyticus, which is valuable for understanding how crustaceans regulate the innate immune system to defend against bacterial infections.

Epigenetic regulation of FOXP3 gene expression in relation to impaired function of regulatory T cells in systemic lupus erythematosus

The impaired function of regulatory T (Treg) cells and the imbalance of Treg/Th17 cells play a central role in developing autoimmune diseases such as systemic lupus erythematosus (SLE). Treg cells are crucial for maintaining immune homeostasis and tolerance to self-antigens. One of the most important transcription factors that regulate the differentiation and function of Treg cells is the FOXP3 protein. Aberrant epigenetic modifications affecting FOXP3 gene expression and consequently dysregulated function of Treg cells have been implicated in the pathogenesis of SLE. Therefore, understanding the intricate interplay between FOXP3 expression pattern in Treg cells and epigenetic regulatory mechanisms (e.g., DNA methylation, histone modifications and non-coding RNAs such as microRNAs and long non-coding RNAs) is crucial for unravelling the underlying mechanisms of SLE. Moreover, targeting these epigenetic pathways may offer novel therapeutic strategies for restoring immune balance and ameliorating autoimmune pathology. This review report aimed to provide an update on the epigenetic controlling of FOXP3 gene expression in SLE disease.

G-Quadruplex Structures as Epigenetic Regulatory Elements in Priming of Defense Genes upon Short-Term Trichoderma atroviride Inoculation in Maize.

Symbiosis establishment between Trichoderma atroviride and plant roots triggers the priming of defense responses, among other effects. Currently, there is no clear evidence regarding the molecular mechanisms that allow the plant to remain alert to future stimulus, either by pathogen attack or any other abiotic stress. Epigenetic modifications have emerged as a strategy to explain the increased defense response of plants in a priming state conferred by Trichoderma. Recently, various non-canonical structures of nucleic acids, especially G-quadruplex structures (G-quadruplexes or G4s), have been identified as potential targets during the establishment or maintenance of plant signals. In the present study, we developed a screening test for the identification of putative G4-forming sequences (PQSs) in previously identified Z. mays priming genes. Bioinformatic analysis revealed the presence of PQSs in the promoter region of five essential genes playing a critical role in priming in maize. Biophysical and spectroscopy studies showed the formation of G4s by these PQSs in vitro, and ChIP assays demonstrate their formation in vivo. Therefore, G4 formation could play a role as an epigenetic regulatory mechanism involved in the long-lasting primed state in maize plants.

CHH hypermethylation contributes to the early ripening of grapes revealed by DNA methylome landscape of “Kyoho” and its bud mutant

Abstract DNA methylation is a stable epigenetic mark that plays a crucial role in plant life processes. However, the specific functions of DNA methylation in grape berry development remain largely unknown. In this study, we performed whole-genome bisulfite sequencing on “Kyoho” grape and its early-ripening bud mutant “Fengzao” at different developmental stages. Our results revealed that transposons (TEs) and gene flanking regions exhibited high levels of methylation, particularly in “Fengzao”, attributed to CHH site methylation. Interestingly, the methylation patterns in these two cultivars showed distinct dynamics during berry development. While methylation levels of genes and TEs increased gradually in “Kyoho” throughout berry development, “Fengzao” did not display consistent changes. Notably, “Fengzao” exhibited higher methylation levels in promoters compared to “Kyoho”, suggesting that hypermethylation of promoters may contribute to its early ripening phenotype. Integration of methylome and transcriptome data highlighted differentially methylated genes (DMGs) and expressed genes (DEGs) associated with secondary metabolite biosynthesis, with 38 genes identified as potential candidates involved in grape berry development. Furthermore, the study identified a jasmonate-induced oxygenase gene (JOX1) as a negative regulator of ripening in Arabidopsis and grapes, indicating that hypermethylation of JOX1 may play a role in the early ripening of “Fengzao”. Overall, our findings provide insights into the distinct DNA methylation patterns during grape berry development, shedding light on the epigenetic regulatory mechanisms underlying the early-ripening bud mutant.

ALKBH5-Mediated m6A Modification of XBP1 Facilitates NSCLC Progression Through the IL-6-JAK-STAT3 Pathway.

The X-box-binding protein 1 (XBP1) is an important transcription factor during endoplasmic reticulum stress response, which was reported as an oncogene in non-small cell lung cancer (NSCLC) tumorigenesis and development. However, the regulatory mechanism of XBP1 expression in NSCLC progression was less reported. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression. This study aimed to investigate the regulatory role of the m6A modification in XBP1 expression in NSCLC. We identified XBP1 as a downstream target of ALKBH5-mediated m6A modification in A549 and PC9 cells. Knockdown of ALKBH5 increased the m6A modification and the stability of XBP1 mRNA, while overexpression of ALKBH5 had the opposite effect. Furthermore, IGF2BP3 was confirmed to be a reader of XBP1 m6A methylation and to enhance the stability of XBP1 mRNA. Additionally, IGF2BP3 knockdown significantly reversed the increase in XBP1 stability mediated by ALKBH5 depletion. In vivo and in vitro experiments demonstrated that ALKBH5/IGF2BP3 promotes the proliferation, migration, and invasion of NSCLC cells by upregulating XBP1 expression. In addition, we also showed that XBP1 promoted NSCLC cell proliferation, migration, and invasion by activating IL-6-JAK-STAT3 signaling. Our research suggested that ALKBH5-mediated m6A modification of XBP1 facilitates NSCLC progression through the IL-6-JAK-STAT3 pathway.

Histone Tail Cleavage as a Mechanism for Epigenetic Regulation.

Histones are essential for DNA packaging and undergo post-translational modifications that significantly influence gene regulation. Among these modifications, histone tail cleavage has recently garnered attention despite being less explored. Cleavage by various proteases impacts processes such as stem cell differentiation, aging, infection, and inflammation, though the mechanisms remain unclear. This review delves into recent insights on histone proteolytic cleavage and its epigenetic significance, highlighting how chromatin, which serves as a dynamic scaffold, responds to signals through histone modification, replacement, and ATP-dependent remodeling. Specifically, histone tail cleavage is linked to critical cellular processes such as granulocyte differentiation, viral infection, aging, yeast sporulation, and cancer development. Although the exact mechanisms connecting histone cleavage to gene expression are still emerging, it is clear that this process represents a novel epigenetic transcriptional mechanism intertwined with chromatin dynamics. This review explores known histone tail cleavage events, the proteolytic enzymes involved, their impact on gene expression, and future research directions in this evolving field.

Epigenetic Regulation in Insect-Microbe Interactions.

Insects have evolved diverse interactions with a variety of microbes, such as pathogenic fungi, bacteria, and viruses. The immune responses of insect hosts, along with the dynamic infection process of microbes in response to the changing host environment and defenses, require rapid and fine-tuned regulation of gene expression programs. Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNA regulation, play important roles in regulating the expression of genes involved in insect immunity and microbial pathogenicity. This review highlights recent discoveries and insights into epigenetic regulatory mechanisms that modulate insect-microbe interactions. A deeper understanding of these regulatory mechanisms underlying insect-microbe interactions holds promise for the development of novel strategies for biological control of insect pests and mitigation of vector-borne diseases.

EPO modified MSCs protects SH-SY5Y cells against ischemia/hypoxia-induced apoptosis via REST-dependent epigenetic remodeling

Hypoxic-ischemic encephalopathy (HIE) is a diffuse brain tissue injury caused by acute ischemia and hypoxia, and it is most commonly found in newborn infants but can also occur in adults. Mesenchymal stem cell (MSC) therapies have showed improved outcomes for treating HIE-induced neuronal defects. However, many key issues associated with poor cell viability and tolerance of grafted MSCs after HIE remain to be resolved. Genetic engineering could endow MSCs with more robust regenerative capacities. Our research, along with that of other scientists, has found that the expression of intracellular erythropoietin (EPO) in human umbilical cord MSCs (hUC-MSCs) increases proportionally with the duration of hypoxia exposure. Furthermore, we observed that EPO, when introduced into the EPO gene-modified hUC-MSCs, can be secreted into the extracellular space. However, the underlying mechanisms that support the neuroprotective effects of EPO-MSCs remain unclear. EPO-MSCs, hUC-MSCs, and NC-MSCs were identified by flow cytometry, osteogenic, and adipogenic differentiation assays. The oxygen-glucose deprivation (OGD)-induced SH-SY5Y cell-line was established, and five groups were set up: control, 24-h ischemia-hypoxia, co-cultured with hUC-MSCs, NC-MSCs, and EPO-MSCs after hypoxia. LEGENDplex™ multi-factor flow cytometry was used to detect the secretion of inflammatory factors in cell supernatants and cerebrospinal fluid. Chromosome-targeted excision and tagging (CUT&Tag) sequencing was applied to detect genomic H3K4me2 modifications, and conjoint analysis with transcriptome sequencing (RNA-seq) was performed. Lentiviral vector infection was used to construct SH-SY5Y cells with stable knockdown of RE1-silencing transcription factor (REST), and flow cytometry was used to detect alterations in apoptosis. Finally, the molecular mechanism underlying the neuroprotective and anti-apoptotic effects of EPO-MSCs was investigated using RNA sequencing, qRT-PCR, and western blot assays. Our results suggest that EPO-MSCs are genetically engineered to secrete significantly more EPO. EPO-MSCs treatment has anti-apoptotic properties and offers neuronal protection during ischemic-hypoxic injury. Furthermore, RNA-seq results suggest that multiple inflammation-related genes were down-regulated after EPO-MSCs treatment. Application of RNA-seq and CUT&Tag combined analysis found that the expressions of REST were significantly up-regulated. Lentiviral vector infection to construct REST knockdown SH-SY5Y failed to rescue apoptosis after hypoxia and co-culture with EPO-MSCs, and SETD2-mediated H3K36me3 protein level expression was reduced. EPO-MSCs may promote neuronal survival by affecting H3K4me2 and thus activating the expression of REST and TET3. EPO-MSCs also upregulated the modification level of SETD2-mediated H3K36me3 and regulated the expression of inflammation-related genes such as PLCG2, as well as apoptosis genes BCL2A1. To investigate the neuroprotective effects of EPO-modified hUC-MSCs and the underlying epigenetic regulatory mechanisms, this study aims to provide a theoretical foundation for the potential application of EPO gene-modified hUC-MSCs in the treatment of HIE.

MicroRNA binding site variants-new potential markers of primary osteoporosis in men and women.

The identification of significant DNA markers of primary osteoporosis may gain new insights by studying genome regions involved in mechanisms of epigenetic regulation through interactions with microRNAs. The authors searched for associations of polymorphic variants of microRNA binding sites of mRNA target genes and polymorphic loci of microRNA genes with primary osteoporosis in a cohort of women and men from the Volga-Ural region of Russia (N = 1.177). Using case-control association analysis, the authors found that rs1061947 (COL1A1), rs10793442 (ZNF239), rs6854081 (FGF2), and rs11614913 (miR-196a) were associated with osteoporotic fractures; rs5854 (MMP1) and rs2910164 (miR-146a) were associated with low bone mineral density; and rs10098470 (TPD52), rs11540149 (VDR), rs1042673 (SOX9), rs1054204 (SPARC), and rs1712 (FBXO5) were markers of both fractures and low bone mineral density. Among the identified associations, ethno specific trends were found, as well as sex-specific associations. Prognostic models were developed, among which the model for predicting osteoporosis in general in women (Area Under Curve = 0.909) achieved the highest level of predictive value. Thus, the potential role of polymorphic variants of microRNA binding sites in the development of primary osteoporosis in men and women from the Volga-Ural region of Russia was demonstrated.

Processing pipelines and analytical methods for single-cell DNA methylation sequencing data.

Single-cell DNA methylation sequencing technology has seen rapid advancements in recent years, playing a crucial role in uncovering cellular heterogeneity and the mechanisms of epigenetic regulation. As sequencing technologies have progressed, the quality and quantity of single-cell methylation data have also increased, making standardized preprocessing workflows and appropriate analysis methods essential for ensuring data comparability and result reliability. However, a comprehensive data analysis pipeline to guide researchers in mining existing data has yet to be established. This review systematically summarizes the preprocessing steps and analysis methods for single-cell methylation data, introduces relevant algorithms and tools, and explores the application prospects of single-cell methylation technology in neuroscience, hematopoietic differentiation, and cancer research. The aim is to provide guidance for researchers in data analysis and to promote the development and application of single-cell methylation sequencing technology.

Viral imitation is the sincerest form of epigenetic flattery.

Viruses use multiple strategies to successfully generate progeny and overcome host defenses. In recent years, it has become increasingly evident that epigenetic mechanisms of host gene regulation are vulnerable to viral manipulation. In the form of histone mimicry, viral invasion of host chromatin is a striking example of how viruses have evolved to invade every aspect of cellular function for viral benefit. In this perspective, we will review how three viruses-influenza A, SARS-CoV-2, and Cotesia plutellae bracovirus-use histone mimicry to promote viral success through immune evasion. These examples highlight the importance of this burgeoning field and point toward the wealth of knowledge we have yet to uncover.

Multi-omics analysis of sea urchin (Strongylocentrotus intermedius) adaptation to salt stress reveals epigenetic regulatory mechanisms

Increased precipitation and surface runoff due to global warming has reduced surface seawater and nearshore water salinity, affecting marine organism survival. Nevertheless, the epigenetic mechanisms underlying the adaptation of sea urchins (Strongylocentrotus intermedius) to low-salinity stress remains unknown. This study utilized response surface methodology to formulate growth models for S. intermedius at different salinity levels and shell diameters. Whole genome bisulphite sequencing, RNA-sequencing, and metabolome analysis were performed on low-salinity stressed sea urchins, and a total of 3006 differential methylated regions, 945 differential methylated genes, 886 differentially expressed genes, and 271 differential metabolites were identified. Multi-omics analysis revealed significant alterations in the gene expression and DNA methylation of key genes (e.g., SPHK2, Arpc1a, and SLC23A1) in S. intermedius under low-salinity stress conditions. These changes subsequently influenced the metabolism of substances, including sphingosine-1-phosphate, ethanolamine phosphate, vitamin C, taurine, and choline. These alterations impacted functions related to immunity, osmoregulation, and energy metabolism in the organism. This study was to comprehensively elucidate the epigenetic mechanisms of S. intermedius under low-salinity stress from the perspective of DNA-RNA-metabolites, providing new insights into salinity adaptation of marine invertebrates.

LncRNA TUG1 regulates mir-34a-5p / SIRT6 to participate in benzene-induced hematotoxicity through PI3K / AKT /mTOR signaling pathway

LncRNA TUG1 plays pivotal roles in various diseases. However, its exact roles in benzene - induced hematotoxicity remain unclear. Herein, we aimed to investigate the role and mechanism of TUG1 in hematoxic injuries caused by benzene. In the current study, TUG1 was found dramatically decreased in WBCs of benzene exposure workers and negatively correlated with benzene exposure duration and urine SPMA. In vitro assays demonstrated that TUG1 overexpression attenuated 1,4-BQ-caused suppression of cell viability and proliferation, and promotion of ROS generation and apoptosis via PI3K/AKT/mTOR pathway. Bioinformatic prediction and molecular assay validated miR-34a-5p was negatively regulated by TUG1. The miR-34a-5p was upregulated in 1,4-BQ treated cells and downregulated in TUG1 overexpression cells. Moreover, miR-34a-5p upregulation partially reversed the protective effects of TUG1 overexpression on 1,4-BQ - caused cytotoxicity. Furthermore, SIRT6 was a downstream target gene of miR-34a-5p, whose expression was reduced in miR-34a-5p upregulation cells and elevated in TUG1 overexpression cells. Upregulated SIRT6 could counteract accelerated cytotoxicity mediated by miR-34a-5p upregulation after 1,4-BQ treatment. Taken together, our study revealed that the critical role of the TUG1/miR-34a-5p/SIRT6 axis in benzene-caused hematotoxicity, and provided scientific basis for further understanding the epigenetic regulatory mechanisms underlying benzene hematotoxicity.