Search Results (375)

Dexamethasone, widely used as an exogenous glucocorticoid in clinical and animal practice, has recently been recognized as an environmental contaminant of concern. Existing evidence documents its ability to induce persistent dyslipidemia in adult offspring. In this study, plasma cholesterol levels in male rats exposed to dexamethasone prenatally (PDE) were increased. Meanwhile, developmental tracking revealed a reduction in hepatic low-density lipoprotein receptor (LDLR) promoter H3K27 acetylation (H3K27ac) and corresponding transcriptional activity across gestational-to-postnatal stages. Mechanistic investigations established glucocorticoid receptor/histone deacetylase2 (GR/HDAC2) axis-mediated epigenetic programming of LDLR through H3K27ac modulation in PDE offspring, potentiating susceptibility to hypercholesterolemia. Additionally, in peripheral blood mononuclear cells (PBMC) of PDE male adult offspring, LDLR H3K27ac level and expression were also decreased and positively correlated with those in the liver. Clinical studies further substantiated that male newborns prenatally treated with dexamethasone exhibited increased serum cholesterol levels and consistent reductions in LDLR H3K27ac levels and corresponding transcriptional activity in PBMC. This study establishes a complete evidence chain linking PDE with epigenetic programming and cholesterol metabolic dysfunction, proposing PBMC epigenetic biomarkers as a novel non-invasive monitoring tool for assessing the developmental toxicity of chemical exposures during pregnancy. This has significant implications for improving environmental health risk assessment systems. Full article

In this study, we investigated the mitochondrial defects resulting from the deletion of GCN5, a lysine-acetyltransferase, in the yeast Saccharomyces cerevisiae. Gcn5 serves as the catalytic subunit of the SAGA acetylation complex and functions as an epigenetic regulator, primarily acetylating N-terminal lysine residues on histones H2B and H3 to modulate gene expression. The loss of GCN5 leads to mitochondrial abnormalities, including defects in mitochondrial morphology, a reduced mitochondrial DNA copy number, and defective mitochondrial inheritance due to the depolarization of actin filaments. These defects collectively trigger the activation of the mitophagy pathway. Interestingly, deleting CSN5, which encodes to Csn5/Rri1 (Csn5), the catalytic subunit of the COP9 signalosome complex, rescues the mitochondrial phenotypes observed in the gcn5Δ strain. Furthermore, these defects are suppressed by exogenous ergosterol supplementation, suggesting a link between the rescue effect mediated by CSN5 deletion and the regulatory role of Csn5 in the ergosterol biosynthetic pathway. Full article

In this study, we identify cortical molecular biomarkers potentially associated with learning in mice using artificial intelligence (AI), inclusive of established and novel feature selection combined with supervised learning technologies. We applied multiple machine learning (ML) algorithms, using public domain ML software, to a public domain dataset, in order to support reproducible findings. We developed technologies tasked with predicting whether a given mouse was shocked to learn, based on protein expression levels extracted from their cortices. Results indicate that it is possible to predict whether a mouse has been shocked to learn or not based only on the following cortical molecular biomarkers: brain-derived neurotrophic factor (BDNF), NR2A subunit of N-methyl-D-aspartate receptor, B-cell lymphoma 2 (BCL2), histone H3 acetylation at lysine 18 (H3AcK18), protein kinase R-like endoplasmic reticulum kinase (pERK), and superoxide dismutase 1 (SOD1). These results were obtained with a novel redundancy-aware feature selection method. Five out of six protein expression biomarkers (BDNF, NR2A, H3AcK18, pERK, SOD1) identified have previously been associated with aspects of learning in the literature. Three of the proteins (BDNF, NR2A, and BCL2) have previously been associated with pruning, and one has previously been associated with apoptosis (BCL2), implying a potential connection between learning and both cortical pruning and apoptosis. The results imply that these six protein expression profiles (BDNF, NR2A, BCL2, H3AcK18, pERK, SOD1) are highly predictive of whether or not a mouse has been shocked to learn. Full article

Objectives: High-calorie diets are linked to increased risks of chronic inflammation and immune dysfunction, yet their role in modulating pneumonia severity remains unclear. Focusing on the interactions among gut-originating short-chain fatty acids (SCFAs), neutrophil function, and histone deacetylases (HDACs), this research examined the exacerbating effects of a high-calorie diet on pneumonia in rats. Methods: Male Sprague-Dawley rats (3 weeks old, 110 ± 10 g) were allocated among four groups: normal diet (N), high-calorie diet (G), LPS-induced pneumonia (P), and high-calorie diet combined with lipopolysaccharide (LPS)-induced pneumonia (GP). LPS was administered via aerosolization for three days. Fecal, serum, and lung SCFA levels were quantified via GC-MS. Neutrophil extracellular traps (NETs) formation, neutrophil apoptosis, and HDAC activity were assessed using immunofluorescence, TUNEL assays, and qRT-PCR. Propionate supplementation and HDAC inhibitor (trichostatin A) interventions were applied to validate mechanistic pathways. Results: The group GP exhibited exacerbated lung inflammation, increased NETs release, and reduced neutrophil apoptosis compared to the group P. Propionate levels in feces, serum, and lung tissues decreased sharply in GP rats, correlating with elevated HDAC1/2/3/6 activity and reduced histone acetylation. Propionate supplementation or HDAC inhibition significantly attenuated lung injury, suppressed NETs, and restored neutrophil apoptosis. Conclusions: High-calorie diets exacerbate pneumonia by depleting gut-derived propionate, which drives HDAC-mediated NETs overproduction and impairs neutrophil apoptosis. Restoring propionate levels or targeting HDACs may offer therapeutic strategies for diet-aggravated respiratory diseases. Mechanistically, propionate-mediated HDAC inhibition demonstrates proof-of-concept efficacy in modulating H4 acetylation, warranting further investigation in disease-specific pneumonia models. Full article

Fusarium verticillioides is a globally prevalent phytopathogenic fungus responsible for multiple diseases in maize and a major producer of the mycotoxin fumonisin B1 (FB1), a highly toxic fungal secondary metabolite (FSM). The histone code, which includes reversible modifications such as acetylation and methylation, plays a critical role in regulating chromatin structure and gene expression. In fungi, di- and tri-methylation of histone H3 at lysine 9 (H3K9me2/3) serves as a key epigenetic mark associated with heterochromatin formation and transcriptional repression. In this study, we identified and characterized a putative heterochromatin protein 1 (HP1) family member in F. verticillioides, designated FvHP1, based on conserved domain architecture and phylogenetic analyses. FvHP1 retains essential residues required for H3K9me2/3 recognition, supporting its functional conservation within the HP1 protein family. Phenotypic analysis of the ΔFvHP1 mutant revealed impaired vegetative growth, reduced conidiation and virulence, and altered FB1 mycotoxin production. Additionally, the accumulation of red pigment in the mutant was linked to the deregulation of secondary metabolism, specifically the overproduction of fusarubin-type naphthoquinones, such as 8-O-methylnectriafurone. These results support the role of FvHP1 in facultative heterochromatin-mediated repression of sub-telomeric biosynthetic gene clusters, including the pigment-associated PGL1 cluster. Our findings provide new insights into the epigenetic regulation of fungal pathogenicity and metabolite production, as well as the first evidence of a functional HP1 homolog in F. verticillioides. Full article

Lysine acetyltransferase 8 (KAT8) is a member of the MYST family of histone acetyltransferases. It catalyzes the acetylation of histone H4 at lysine 16 (H4K16ac) and non-histone proteins. Abnormal upregulation or downregulation of KAT8 and its associated H4K16ac have been observed in malignant tumors, suggesting its close association with tumorigenesis and progression. Characterized by structural diversity and multi-target mechanisms, natural agents have been increasingly shown to possess significant antitumor activity. This review focuses on KAT8, summarizing its molecular mechanisms in regulating tumor development by catalyzing substrate protein acetylation, which impacts tumor cell proliferation, cell cycle regulation, apoptosis, DNA damage repair, and autophagy. It also systematically discusses the pharmacological activities and molecular mechanisms of small-molecule agents that target KAT8 to inhibit tumor proliferation, including natural compounds, synthetic drugs, and non-coding RNAs. Full article

Background/Objectives: Chronic craniofacial inflammation is recognized as a factor in anxiety-like behaviors, yet effective therapeutic options remain limited. Agmatine, a dietary bioactive compound found in fermented foods such as sake lees, exhibits modulatory effects on neural functions, alleviating psychological distress like anxiety associated with local inflammation. Methods: We investigated both the therapeutic and preventive effects of agmatine on anxiety-like behaviors and the related neural basis in a mouse model of persistent craniofacial inflammation induced by complete Freund’s adjuvant (CFA). Results: Comprehensive behavioral assessments, including the elevated plus maze, open field, dark–light box, social interaction, and novel object recognition tests, revealed that therapeutic agmatine administration (1.0 and 30 mg/kg) significantly reduced CFA-induced anxiety-like behaviors, with the higher dose showing more robust and sustained effects across multiple time points. These behavioral improvements were paralleled by reductions in acetylated histone H3, FosB, and c-Fos expression in key anxiety-related brain regions, suggesting a reversal of craniofacial inflammation-associated neural changes. In contrast, preventive agmatine treatment exerted modest and time-dependent behavioral benefits with minimal molecular normalization. Notably, preventive agmatine did not affect general locomotor activity (indicated by total movement distance), indicating that its anxiolytic effects were not confounded by altered locomotor activity. Metabolomic analysis confirmed the presence of agmatine in sake lees (~0.37 mM), supporting the hypothesis that fermented food products might offer dietary routes to emotional resilience. Conclusions: These findings underscore agmatine’s promise as a context-specific epigenetic modulator capable of mitigating anxiety-like behaviors by normalizing inflammation-driven molecular dysregulation in the brain. Full article

Background: The epigenetic regulation of adipogenic differentiation in dental stem cells (DSCs) remains poorly understood, as research has prioritized osteogenic differentiation for dental applications. However, elucidating these mechanisms could enable novel regenerative strategies for soft tissue engineering. Periodontal ligament stem cells (PDLSCs) exhibit notable adipogenic potential, possibly linked to histone 3 acetylation at lysine 9 (H3K9ac); however, the mechanistic role of this modification remains unclear. Methods: To address this gap, we investigated how histone deacetylase inhibitors (HDACis)—valproic acid (VPA, 8 mM) and trichostatin A (TSA, 100 nM)—modulate H3K9ac dynamics, adipogenic gene expression (C/EBPβ and PPARγ-2), and chromatin remodeling during PDLSCs differentiation. Techniques used included quantitative PCR (qPCR), lipid droplet analysis, and chromatin immunoprecipitation followed by qPCR (ChIP-qPCR). Results: TSA-treated cells exhibited increased lipid deposition with smaller lipid droplets compared to VPA-treated cells. Global H3K9ac levels correlated positively with adipogenic progression. VPA induced early upregulation of C/EBPβ and PPARγ-2 (day 7), whereas TSA triggered a delayed but stronger PPARγ-2 expression. ChIP-qPCR analysis revealed significant H3K9ac enrichment at the PPARγ-2 promoter in TSA-treated cells, indicating enhanced chromatin accessibility. Conclusions: These findings demonstrate that H3K9ac-mediated epigenetic remodeling plays a critical role in the adipogenic differentiation of PDLSCs and identifies TSA as a potential tool for modulating this process. Full article

The human (h) growth hormone (GH)/placental lactogen (PL) gene family has served as an important model to study tissue-specific expression. The two GH genes (hGH-N/GH1 and GH-V/GH2) and three PL or chorionic somatomammotropin hormone (CSH) genes (hPL-L/CSL1, hPL-A/CSH1 and hPL-B/CSH2) are clustered together at a single locus. Although they share >90% sequence similarity, hGH-N is expressed by somatotrophs of the anterior pituitary while the remaining four hGH/PL genes are expressed by the villous syncytiotrophoblast of the placenta. Efficient pituitary expression depends on a locus control region (LCR) that includes nuclease hypersensitive sites I-V (HS I-V). For activation, data indicate that HS III facilitates the initial access of pituitary-specific transcription factor Pit-1 to the locus, where it is required to bind Pit-1 sites at HS I/II and the hGH-N promoter. This is associated with histone acetylation and tri-methylation modifications that are consistent with active chromatin. However, all five hGH/PL genes share similar nuclease sensitivity in human pituitary chromatin, suggesting similar levels of accessibility and thus potential for transcription. Furthermore, hPL-A and hPL-B promoters contain Pit-1 binding sites, and the hPL-A promoter, like hGH-N, will support expression in transfected pituitary tumor GC cells in culture. These observations suggest the possibility of a transcriptional repressor mechanism that prevents hPL gene expression in the pituitary. P sequences were identified as a candidate. They are located upstream of all four placental hGH/PL genes but not hGH-N, repress hPL-A promoter activity in transfected pituitary GC cells, and bind a forkhead box A1/nuclear factor-1 transcription, which is proposed to act as a repressor complex in human pituitary chromatin. In spite of this, the inability to limit hGH-N expression when tested in transgenic mice brought the role of P sequences in pituitary repression into question. These observations are re-examined here in light of new evidence that the LCR (HS III) interacts with P sequences in the human pituitary. Full article

This study investigated whether the supplementation of prebiotic inulin to gestating sows programmatically affects offspring growth performance and meat quality while exploring its epigenetic effects through histone acetylation modulation. After mating, sixty multiparous sows (Landrace × Yorkshire; parity 2–3) were assigned to a 2 × 2 factorial arrangement with inulin (0% vs. 1.5%) and fat (0% or 5%) supplementation until farrowing. Post-weaning, five litters (10 piglets per litter) per treatment were selected and maintained in their original litter for fattening under standardized feeding. The results demonstrated that maternal inulin supplementation during gestation accomplished the following: (1) Increased offspring liver index by 13.4% at weaning and 6.8% at finishing (p < 0.05) while reducing the finishing-phase backfat thickness by 11.6% (p < 0.01), with a significant inulin × fat interaction attenuating fat-induced abdominal lipid accumulation at weaning (p = 0.05). (2) Decreased longissimus dorsi muscle lightness (L*) by 4.5% in finishing pigs (p = 0.02) without altering the other meat quality parameters. (3) Suppressed offspring liver lipid deposition at birth and finishing (p < 0.05), concomitant with upregulated hepatic PGC-1α and CPT1A expression (p < 0.05). (4) Elevated neonatal serum butyrate by 15.6% (p = 0.06) while inhibiting hepatic histone deacetylase (HDAC) activity and enhancing histone H3/H4 acetylation (p < 0.01). These findings suggest that maternal inulin supplementation during gestation mitigates offspring hepatic lipid deposition through butyrate-mediated epigenetic regulation, where microbial-derived butyrate from inulin fermentation inhibits HDAC activity, enhances histone acetylation levels, and upregulates fatty acid β-oxidation gene expression. This study provides novel mechanistic insights into how maternal dietary fiber nutrition programs offspring development through epigenetic reprogramming. Full article

Background: Dynamic changes in histone acetylation play crucial roles during cellular differentiation and disease development, but their detection in living cells is still a challenging task. Objectives: Here, we developed a Bimolecular Anchor Detector (BiAD) sensor for the detection of locus-specific changes in histone acetylation in living cells by fluorescence microscopy. Methods: We used the BRD9 bromodomain cloned as tandem double domain (2xBRD9-BD) as a reader of histone acetylation. It was integrated into a dual-color BiAD chassis that was previously described by us. Results: We identified the gene body of TTC34 as a potential target for our sensor, because it contains dense histone acetylation and 392 local sequence repeats. Using a binding-deficient mutant of 2xBRD9-BD as a negative control, we established a successful readout of histone acetylation at the TTC34 locus. A single-domain reader did not function, indicating the requirement for the double reader to enhance the affinity and specificity of the chromatin interaction via avidity effects. With this sensor, we could detect dynamic increases in histone acetylation at the TTC34 locus after the treatment of cells with the histone deacetylase inhibitor Trichostatin A for 6 h indicating the applicability of the sensor for single-cell epigenome studies. Conclusions: Our data demonstrate that active chromatin modifications can be detected by BiAD sensors using 2xBRD9-BD as a reader. This complements the toolkit of the available BiAD sensors and documents the modularity of BiAD sensors. Full article

Abnormal epigenetic reprogramming of nuclear-transferred (NT) embryos leads to the limited efficiency of producing cloned animals. Trichostatin A (TSA), a histone deacetylase inhibitor, improves NT embryo development, but its role in histone acetylation in porcine embryos cloned with mesenchymal stem cells (MSCs) is not fully understood. This study aimed to compare the effects of TSA on embryo development, histone acetylation patterns, and key epigenetic-related genes between in vitro fertilization (IVF), NT-MSC, and 40 nM TSA-treated NT-MSC (T-NT-MSC). The results demonstrated an increase in the blastocyst rate from 13.7% to 32.5% in the T-NT-MSC, and the transcription levels of CDX2, NANOG, and IGF2R were significantly elevated in T-NT-MSC compared to NT-MSC. TSA treatment also led to increased fluorescence intensity of acH3K9 and acH3K18 during early embryo development but did not differ in acH4K12 levels. The expression of epigenetic-related genes (HDAC1, HDAC2, CBP, p300, DNMT3a, and DNMT1) in early pre-implantation embryos followed a pattern similar to IVF embryos. In conclusion, TSA treatment improves the in vitro development of porcine embryos cloned with MSCs by increasing histone acetylation, modifying chromatin structure, and enhancing the expression of key genes, resulting in profiles similar to those of IVF embryos. Full article

Background: Histone deacetylases (HDACs) are enzymes that deacetylate histone proteins, impacting the transcriptional repression and activation of cancer-associated genes such as P53 and Ras. The overexpression of HDACs in breast cancer (BC) underscores their significance as therapeutic targets for modulating gene expression through epigenetic regulation. Methods: In this study, a novel series of SAHA (suberoylanilide hydroxamic acid) analogs were designed using an in silico ligand-based strategy. These analogs were then synthesized and evaluated for their HDAC-inhibitory capacity as well as their antiproliferative capacity on breast cancer cells. These compounds retained an aliphatic LINKER, mimicking the natural substrate acetyl-lysine, while differing from the hydroxamic fragment present in SAHA. Results: The synthesized compounds exhibited HDAC inhibitory activity, suggesting potential for binding to these pharmacological targets. Compounds 5b, 6a, and 6b were identified as promising candidates in the evaluation on breast cancer cell lines MCF-7 and MDA-MB-231 at 72 h. Specifically, compound 6b, which contains an N-trifluoroacetyl group as a zinc-binding group (ZBG), demonstrated an IC₅₀ of 76.7 µM in the MDA-MB-231 cell line and 45.7 µM in the MCF-7 cell line. In the non-tumorigenic cell line, the compound exhibited an IC₅₀ of 154.6 µM. Conversely, SAHA exhibited an almost negligible safety margin with regard to its cytotoxic activity when compared to breast cancer cells and healthy cells (MCF-10A). This observation underscores the elevated toxicity exhibited by hydroxamic acid-derived molecules. Conclusions: The bioisosteric modification of ZBG by N-trifluoroacetyl in 6a and 6b demonstrated favorable cytotoxic activity, exhibiting a higher safety margin. This study underscores the challenge of identifying novel ZBGs to replace hydroxamic acid in the development of HDAC inhibitors, with the objective of enhancing their physicochemical and toxicological profile for utilization in BC treatment. Full article

Nitric oxide (NO) is a gaseous free radical known to modulate plant metabolism through crosstalk with phytohormones (especially ABA, SA, JA, and ethylene) and other signaling molecules (ROS, H₂S, melatonin), and to regulate gene expression (by influencing DNA methylation and histone acetylation) as well as protein function through post-translational modifications (cysteine S-nitrosation, metal nitrosation, tyrosine nitration, nitroalkylation). Recently, NO has gained attention as a molecule promoting crop resistance to stress conditions. Herein, we review innovations from the NO field and nanotechnology on an up-to-date phytopathological background. Full article

Brain injuries can result from accidents, warfare, sports injuries, or brain diseases. Identifying regeneration-associated genes (RAGs) during epigenome remodeling upon brain injury could have a significant impact on reducing neuronal death and subsequent neurodegeneration for patients with brain injury. We previously identified several WNT genes as RAGs involved in the neurite regrowth of injured cortical neurons. Among them, the expression of the Wnt8a gene increased most significantly during neurite regrowth, indicating its potential to promote neuronal regeneration. In this study, we investigated the regulatory mechanism of Wnt8a transcription. An algorithm was developed to predict the novel enhancer regions of candidate genes. By combining active enhancer marks, histone H3 lysine 27 acetylation (H3K27ac), and histone H3 lysine 4 mono-methylation (H3K4me1), we identified a candidate enhancer region for Wnt8a located 1.7 Mb upstream and 0.1 Mb downstream of the Wnt8a gene. This region was organized into enhancers (Ens) 1–15. Enhancer RNA expression from the predicted En1–15 regions, DNA topological dynamics, and the activity of predicted enhancers were analyzed to validate the candidate active enhancers. Our findings showed that the En8, 9, 10, 14, and 15 regions expressed higher eRNAs during neurite regrowth. Notably, the En8-2 and En14-2 subregions showed significantly up-regulated H3K4me1 modification during neurite regrowth. Using chromatin conformation capture assays and enhancer–reporter assays, we delineated that the molecular regulation of Wnt8a transcription during neurite regrowth occurs through looped En8-promoter interplay. Full article