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Keywords = histone acetylation

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17 pages, 3846 KiB  
Article
The Enhancer–Promoter-Mediated Wnt8a Transcription During Neurite Regrowth of Injured Cortical Neurons
by Shr-Han Weng, Wen-Ling Liao and Linyi Chen
Cells 2025, 14(5), 319; https://doi.org/10.3390/cells14050319 - 20 Feb 2025
Viewed by 182
Abstract
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 [...] Read more.
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
(This article belongs to the Section Cells of the Nervous System)
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10 pages, 1290 KiB  
Article
Effect of Curcumin Pretreatment on the Susceptibility of Cryptococcus neoformans to Photodynamic Therapy Mediated by Aluminum Phthalocyanine in Nanoemulsion
by Fabiana Chagas Costa, Lourival Carvalho Nunes, Kunal Ranjan, Ariane Pandolfo Silveira, Ingrid Gracielle Martins da Silva, André de Lima e Silva Mariano, Paulo Eduardo Narcizo de Souza, Sônia Nair Báo, Marcio Jose Poças-Fonseca and Luis Alexandre Muehlmann
Pharmaceuticals 2025, 18(2), 240; https://doi.org/10.3390/ph18020240 - 11 Feb 2025
Viewed by 504
Abstract
Background/Objectives: Curcumin has antimicrobial activity, and its mechanism of action involves changing histone acetylation. Our group has shown that histone deacetylases (HDACs) inhibitors increase the sensibility of Cryptococcus neoformans to certain antifungal treatments. Therefore, the aim of this work was to investigate whether [...] Read more.
Background/Objectives: Curcumin has antimicrobial activity, and its mechanism of action involves changing histone acetylation. Our group has shown that histone deacetylases (HDACs) inhibitors increase the sensibility of Cryptococcus neoformans to certain antifungal treatments. Therefore, the aim of this work was to investigate whether curcumin pretreatment increases the effect of photodynamic therapy (PDT) mediated by aluminum phthalocyanine in nanoemulsion (AlPc-NE) against C. neoformans. Methods: The minimum inhibitory concentrations (MIC) of AlPc-NE and curcumin, along with the 72-h growth curve of cells exposed to the combined treatments, were evaluated in the C. neoformans reference strain H99. Additionally, further analysis was performed using HDAC gene deletion mutant strains, hda1Δ and hos2Δ. Results: Curcumin reduces the effect of PDT on C. neoformans reference strain H99, likely due to its antioxidant properties. In the hda1Δ strain, 50% MIC of curcumin reduced the effect of PDT, but this effect was not observed in response to 75% MIC of curcumin. Conversely, in the hos2Δ strain, pretreatment with curcumin at 75% MIC enhanced the efficacy of PDT in combination with 50% MIC of AlPc-NE. Conclusions: These results indicate that curcumin inhibits C. neoformans. Moreover, at lower concentrations, curcumin protects cells against oxidant damage, while at higher concentrations, it may trigger epigenetic mechanisms that compromise cell viability. In conclusion, both curcumin and PDT are active against C. neoformans, with HDACs affecting their efficacy, and the effectiveness of the combined treatment depends on the concentration of both curcumin and AlPc-NE. Full article
(This article belongs to the Section Pharmaceutical Technology)
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15 pages, 1003 KiB  
Review
Adaptable Alchemy: Exploring the Flexibility of Specialized Metabolites to Environmental Perturbations Through Post-Translational Modifications (PTMs)
by Luca Cimmino, Annalisa Staiti, Domenico Carputo, Teresa Docimo, Vincenzo D’Amelia and Riccardo Aversano
Plants 2025, 14(3), 489; https://doi.org/10.3390/plants14030489 - 6 Feb 2025
Viewed by 515
Abstract
Plants are subjected to various stresses during the growth process, including biotic stresses, as well as abiotic stresses such as temperature, drought, salt, and heavy metals. To cope with these biotic and abiotic adversities, plants have evolved complex regulatory mechanisms during their long-term [...] Read more.
Plants are subjected to various stresses during the growth process, including biotic stresses, as well as abiotic stresses such as temperature, drought, salt, and heavy metals. To cope with these biotic and abiotic adversities, plants have evolved complex regulatory mechanisms during their long-term environmental adaptations. In a suddenly changing environment, protein modifiers target other proteins to induce post-translational modification (PTM) in order to maintain cell homeostasis and protein biological activity in plants. PTMs modulate the activity of enzymes and transcription factors in their respective metabolic pathways, enabling plants to produce essential compounds for their survival under stress conditions. Examples of post-translational mechanisms include phosphorylation, ubiquitination, glycosylation, acetylation, protein–protein interactions, and targeted protein degradation. Furthermore, the role of histone modifications in regulating secondary metabolism deserves attention due to its potential impact on heritability and its contribution to stress tolerance. Understanding the epigenetic aspect of these modifications can provide valuable insights into the mechanisms underlying stress response. In this context, also examining PTMs that impact the biosynthesis of secondary metabolites is meaningful. Secondary metabolites encompass a wide range of compounds such as flavonoids, alkaloids, and terpenoids. These secondary metabolites play a crucial role in plant defense against herbivores, pathogens, and oxidative stress. In this context, it is imperative to understand the contribution of secondary metabolism to plant tolerance to abiotic stresses and how this understanding can be leveraged to improve long-term survival. While many studies have focused on the transcriptional regulation of these metabolites, there is a growing interest in understanding various changes in PTMs, such as acetylation, glycosylation, and phosphorylation, that are able to modulate plants’ response to environmental conditions. In conclusion, a comprehensive exploration of post-translational mechanisms in secondary metabolism can enhance our understanding of plant responses to abiotic stress. This knowledge holds promise for future applications in genetic improvement and breeding strategies aimed at increasing plant resilience to environmental challenges. Full article
(This article belongs to the Special Issue Protein Metabolism in Plants and Algae under Abiotic Stress)
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26 pages, 1546 KiB  
Review
Cellular Epigenetic Targets and Epidrugs in Breast Cancer Therapy: Mechanisms, Challenges, and Future Perspectives
by Ibrahim S. Alalhareth, Saleh M. Alyami, Ali H. Alshareef, Ahmed O. Ajeibi, Manea F. Al Munjem, Ahmad A. Elfifi, Meshal M. Alsharif, Seham A. Alzahrani, Mohammed A. Alqaad, Marwa B. Bakir and Basel A. Abdel-Wahab
Pharmaceuticals 2025, 18(2), 207; https://doi.org/10.3390/ph18020207 - 3 Feb 2025
Viewed by 874
Abstract
Breast cancer is the most common malignancy affecting women, manifesting as a heterogeneous disease with diverse molecular characteristics and clinical presentations. Recent studies have elucidated the role of epigenetic modifications in the pathogenesis of breast cancer, including drug resistance and efflux characteristics, offering [...] Read more.
Breast cancer is the most common malignancy affecting women, manifesting as a heterogeneous disease with diverse molecular characteristics and clinical presentations. Recent studies have elucidated the role of epigenetic modifications in the pathogenesis of breast cancer, including drug resistance and efflux characteristics, offering potential new diagnostic and prognostic markers, treatment efficacy predictors, and therapeutic agents. Key modifications include DNA cytosine methylation and the covalent modification of histone proteins. Unlike genetic mutations, reprogramming the epigenetic landscape of the cancer epigenome is a promising targeted therapy for the treatment and reversal of drug resistance. Epidrugs, which target DNA methylation and histone modifications, can provide novel options for the treatment of breast cancer by reversing the acquired resistance to treatment. Currently, the most promising approach involves combination therapies consisting of epidrugs with immune checkpoint inhibitors. This review examines the aberrant epigenetic regulation of breast cancer initiation and progression, focusing on modifications related to estrogen signaling, drug resistance, cancer progression, and the epithelial–mesenchymal transition (EMT). It examines existing epigenetic drugs for treating breast cancer, including agents that modify DNA, inhibitors of histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone demethyltransferases. It also delves into ongoing studies on combining epidrugs with other therapies and addresses the upcoming obstacles in this field. Full article
(This article belongs to the Section Pharmacology)
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14 pages, 2747 KiB  
Article
Melatonin Modulates ZAP70 and CD40 Transcripts via Histone Modifications in Canine Ileum Epithelial Cells
by Jian Hong, Saber Y. Adam, Shiqi Wang, Hao Huang, In Ho Kim, Abdelkareem A. Ahmed, Hao-Yu Liu and Demin Cai
Vet. Sci. 2025, 12(2), 87; https://doi.org/10.3390/vetsci12020087 - 23 Jan 2025
Viewed by 633
Abstract
Melatonin (MLT), produced by the pineal gland and other tissues, is known for its anti-inflammatory effects, particularly in regulating inflammatory markers and cytokines in intestinal cells. Our study aimed to investigate how MLT influences the expression of inflammatory genes through histone modification in [...] Read more.
Melatonin (MLT), produced by the pineal gland and other tissues, is known for its anti-inflammatory effects, particularly in regulating inflammatory markers and cytokines in intestinal cells. Our study aimed to investigate how MLT influences the expression of inflammatory genes through histone modification in canine ileum epithelial cells (cIECs). In our experiment, cIECs were cultured and divided into a control group (CON) and an MLT-treatment group. MLT did not significantly affect cell growth or death in cIECs compared to the CON. However, MLT treatment led to an upregulation of CD40, ZAP70, and IL7R and a downregulation of LCK, RPL37, TNFRSF13B, CD4, CD40LG, BLNK, and CIITA at the mRNA expression level. Moreover, MLT significantly altered the NF-kappa B signaling pathway by upregulating genes, such as CD40, ZAP70, TICAM1, VCAMI, GADD45B, IRAK1, TRADD, RELA, RIPK1, and RELB, and downregulating PRKCB, LY96, CD40LG, ILIB, BLNK, and TNFRSF11A. Using ChIP-qPCR, we discovered that MLT treatment enhanced histone acetylation marks H3K9ac, H3K18ac, H3K27ac, and methylation marks H3K4me1 and H3K4me3 at the ZAP70 and CD40 gene loci (p < 0.05). Additionally, the enrichment of RNA polymerase II and phosphorylated Ser5 pol-II at these loci was increased in MLT-treated cells (p < 0.05), indicating heightened transcriptional activity. In conclusion, our findings suggest that MLT mitigates inflammation in cIECs by modulating the transcription of ZAP70 and CD40 through histone modifications, offering potential therapeutic insights for inflammatory bowel diseases. Full article
(This article belongs to the Topic Research on Companion Animal Nutrition)
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20 pages, 4939 KiB  
Article
Genome-Wide Identification and Characterization of Histone Acetyltransferases and Deacetylases in Cucumber, and Their Implication in Developmental Processes
by Agnieszka Skarzyńska-Łyżwa, Szymon Turek, Maksymilian Pisz, Aparna, Wojciech Pląder and Magdalena Pawełkowicz
Genes 2025, 16(2), 127; https://doi.org/10.3390/genes16020127 - 23 Jan 2025
Viewed by 511
Abstract
Background/Objectives: Cucumber (Cucumis sativus) provides a model for exploring the molecular basis of sex determination, particularly the regulation of floral organ differentiation through gene expression. This complex process is modulated by epigenetic factors, such as histone acetyltransferases (HATs) and histone deacetylases [...] Read more.
Background/Objectives: Cucumber (Cucumis sativus) provides a model for exploring the molecular basis of sex determination, particularly the regulation of floral organ differentiation through gene expression. This complex process is modulated by epigenetic factors, such as histone acetyltransferases (HATs) and histone deacetylases (HDACs), which respectively activate and repress gene transcription by adding or removing acetyl groups from histone proteins. Despite their known functions, the roles of HATs and HDACs throughout cucumber’s floral developmental stages remain unclear. Methods: In this study, we conducted a genome-wide analysis of HAT and HDAC gene families in cucumber, examining their phylogenetic relationships, gene structures, protein domains, and expression profiles across various stages of floral development. Results: We identified 36 CsHAT and 12 CsHDAC genes, grouping them into families with evolutionary counterparts in other plant species. RNA sequencing revealed stage-specific expression patterns, suggesting dynamic roles for these gene families in floral organ development. Conclusions: These findings contribute valuable insights into the epigenetic regulation of gene expression in cucumber flower formation, presenting avenues for further research on the genetic control of plant reproductive development. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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16 pages, 6503 KiB  
Article
HDC1 Promotes Primary Root Elongation by Regulating Auxin and K+ Homeostasis in Response to Low-K+ Stress
by Xiaofang Kuang, Hao Chen, Jing Xiang, Juan Zeng, Qing Liu, Yi Su, Chao Huang, Ruozhong Wang, Wanhuang Lin and Zhigang Huang
Biology 2025, 14(1), 57; https://doi.org/10.3390/biology14010057 - 12 Jan 2025
Viewed by 650
Abstract
Plants frequently encounter relatively low and fluctuating potassium (K+) concentrations in soil, with roots serving as primary responders to this stress. Histone modifications, such as de-/acetylation, can function as epigenetic markers of stress-inducible genes. However, the signaling network between histone modifications [...] Read more.
Plants frequently encounter relatively low and fluctuating potassium (K+) concentrations in soil, with roots serving as primary responders to this stress. Histone modifications, such as de-/acetylation, can function as epigenetic markers of stress-inducible genes. However, the signaling network between histone modifications and low-K+ (LK) response pathways remains unclear. This study investigated the regulatory role of Histone Deacetylase Complex 1 (HDC1) in primary root growth of Arabidopsis thaliana under K+ deficiency stress. Using a hdc1-2 mutant line, we observed that HDC1 positively regulated root growth under LK conditions. Compared to wild-type (WT) plants, the hdc1-2 mutant exhibited significantly inhibited primary root growth under LK conditions, whereas HDC1-overexpression lines displayed opposite phenotypes. No significant differences were observed under HK conditions. Further analysis revealed that the inhibition of hdc1-2 on root growth was due to reduced apical meristem cell proliferation rather than cell elongation. Notably, the root growth of hdc1-2 showed reduced sensitivity compared to WT after auxin treatment under LK conditions. HDC1 may regulate root growth by affecting auxin polar transport and subsequent auxin signaling, as evidenced by the altered expression of auxin transport genes. Moreover, the organ-specific RT-qPCR analyses unraveled that HDC1 negatively regulates the expression of CBL-CIPK-K+ channel-related genes such as CBL1, CBL2, CBL3, AKT1, and TPK1, thereby establishing a molecular link between histone deacetylation, auxin signaling, and CBLs-CIPKs pathway in response to K+ deficiency. Full article
(This article belongs to the Section Plant Science)
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22 pages, 2033 KiB  
Review
Butyrate Supplementation Improves Intestinal Health and Growth Performance in Livestock: A Review
by Wenting Chen, Qingshan Ma, Yan Li, Lin Wei, Zhenwei Zhang, Adnan Khan, Muhammad Zahoor Khan and Changfa Wang
Biomolecules 2025, 15(1), 85; https://doi.org/10.3390/biom15010085 - 8 Jan 2025
Viewed by 1176
Abstract
Butyrate supplementation has gained considerable attention for its potential benefits in livestock, particularly concerning intestinal health and growth performance. This review synthesizes recent research on the diverse roles of butyrate, across various livestock species. As a short-chain fatty acid, butyrate is known for [...] Read more.
Butyrate supplementation has gained considerable attention for its potential benefits in livestock, particularly concerning intestinal health and growth performance. This review synthesizes recent research on the diverse roles of butyrate, across various livestock species. As a short-chain fatty acid, butyrate is known for enhancing intestinal development, improving immune function, and modulating microbial diversity. Studies indicate that butyrate supports gut barrier integrity, reduces inflammation, and optimizes feed efficiency, especially during the critical weaning and post-weaning periods in calves, piglets, and lambs. Supplementation with butyrate in livestock has been shown to increase average daily gain (ADG), improve gut microbiota balance, promote growth, enhance gut health, boost antioxidant capacity, and reduce diarrhea. Additionally, butyrate plays a role in the epigenetic regulation of gene expression through histone acetylation, influencing tissue development and immune modulation. Its anti-inflammatory and antioxidant effects have been demonstrated across various species, positioning butyrate as a potential therapeutic agent in animal nutrition. This review suggests that optimizing butyrate supplementation strategies to meet the specific needs of each species may yield additional benefits, establishing butyrate as an important dietary additive for enhancing growth performance and health in livestock. Full article
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9 pages, 1376 KiB  
Brief Report
A High-Fat Diet Induces Epigenetic 1-Carbon Metabolism, Homocystinuria, and Renal-Dependent HFpEF
by Suresh C. Tyagi
Nutrients 2025, 17(2), 216; https://doi.org/10.3390/nu17020216 - 8 Jan 2025
Viewed by 1022
Abstract
Background/Objectives: Chronic gut dysbiosis due to a high-fat diet (HFD) instigates cardiac remodeling and heart failure with preserved ejection fraction (HFpEF), in particular, kidney/volume-dependent HFpEF. Studies report that although mitochondrial ATP citrate lyase (ACLY) supports cardiac function, it decreases more in human HFpEF [...] Read more.
Background/Objectives: Chronic gut dysbiosis due to a high-fat diet (HFD) instigates cardiac remodeling and heart failure with preserved ejection fraction (HFpEF), in particular, kidney/volume-dependent HFpEF. Studies report that although mitochondrial ATP citrate lyase (ACLY) supports cardiac function, it decreases more in human HFpEF than HFrEF. Interestingly, ACLY synthesizes lipids and creates hyperlipidemia. Epigenetically, ACLY acetylates histone. The mechanism(s) are largely unknown. Methods/Results: One hypothesis is that an HFD induces epigenetic folate 1-carbon metabolism (FOCM) and homocystinuria. This abrogates dipping in sleep-time blood pressure and causes hypertension and morning heart attacks. We observed that probiotics/lactobacillus utilize fat/lipids post-biotically, increasing mitochondrial bioenergetics and attenuating HFpEF. We suggest novel and paradigm-shift epigenetic mitochondrial sulfur trans-sulfuration pathways that selectively target HFD-induced HFpEF. Previous studies from our laboratory, using a single-cell analysis, revealed an increase in the transporter (SLC25A) of s-adenosine–methionine (SAM) during elevated levels of homocysteine (Hcy, i.e., homocystinuria, HHcy), a consequence of impaired epigenetic recycling of Hcy back to methionine due to an increase in the FOCM methylation of H3K4, K9, H4K20, and gene writer (DNMT) and decrease in eraser (TET/FTO). Hcy is transported to mitochondria by SLC7A for clearance via sulfur metabolomic trans-sulfuration by 3-mercaptopyruvate sulfur transferase (3MST). Conclusions: We conclude that gut dysbiosis due to HFD disrupts rhythmic epigenetic memory via FOCM and increases in DNMT1 and creates homocystinuria, leading to a decrease in mitochondrial trans-sulfuration and bioenergetics. The treatment with lactobacillus metabolites fat/lipids post-biotically and bi-directionally produces folic acid and lactone–ketone body that mitigates the HFD-induced mitochondrial remodeling and HFpEF. Full article
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20 pages, 3094 KiB  
Article
Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres
by Natália Hogetop Freire, Alice Laschuk Herlinger, Julia Vanini, Matheus Dalmolin, Marcelo A. C. Fernandes, Carolina Nör, Vijay Ramaswamy, Caroline Brunetto de Farias, André Tesainer Brunetto, Algemir Lunardi Brunetto, Lauro José Gregianin, Mariane da Cunha Jaeger, Michael D. Taylor and Rafael Roesler
Cells 2025, 14(2), 72; https://doi.org/10.3390/cells14020072 - 7 Jan 2025
Viewed by 964
Abstract
Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could [...] Read more.
Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced MYC while increasing TP53 expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genes TUBB3 and ENO2. The expression of stemness genes SOX2, NES, and PRTG was differentially affected by VPA in MB cells with different TP53 status. VPA increased H3K9 occupancy of the promoter region of TP53. Among the genes regulated by VPA, the stemness regulators MYC and NES showed an association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in the modulation of stemness, neuronal differentiation, and the expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in the expression of MYC and an increase in TP53. Full article
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16 pages, 2511 KiB  
Article
Phyllanthus emblica Prevents Adipogenesis by Regulating Histone Acetylation
by Seon Kyeong Park, Yu Geon Lee, Jae-In Lee, Min-Sun Kim, Jae-Ho Park, Jin-Taek Hwang and Min-Yu Chung
Foods 2025, 14(2), 160; https://doi.org/10.3390/foods14020160 - 7 Jan 2025
Viewed by 695
Abstract
Phyllanthus emblica is widely used in Ayurvedic preparations against multiple disorders and contains various bioactive components. This study aimed to determine the preventive effect of P. emblica on obesity by evaluating the inhibition of adipogenesis and the related regulatory epigenetic mechanisms during 3T3-L1 [...] Read more.
Phyllanthus emblica is widely used in Ayurvedic preparations against multiple disorders and contains various bioactive components. This study aimed to determine the preventive effect of P. emblica on obesity by evaluating the inhibition of adipogenesis and the related regulatory epigenetic mechanisms during 3T3-L1 differentiation. The ethyl acetate fraction of P. emblica (EFPE) effectively inhibited lipid accumulation and triglyceride (TG) production in 3T3-L1 adipocytes. It also inhibited histone acetyltransferase (HAT) activity and regulated Pcaf-specific H3K9 acetylation and the expression of adipogenesis-related genes during adipocyte differentiation. Phenolic compounds were the main components of EFPE, of which gallic acid (GA) exhibited the strongest inhibitory effect on lipid accumulation and TG production. Notably, GA effectively regulated adipogenesis-mediated gene expression through H3K9 acetylation. These findings, along with the experiment results, suggest that EFPE containing GA is a potent agent for preventing obesity by regulating H3K9 acetylation. Full article
(This article belongs to the Special Issue The Development of New Functional Foods and Ingredients: 2nd Edition)
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12 pages, 3119 KiB  
Article
Epigenetic Inhibitors Differentially Impact TGF-β1 Signaling Cascades in COPD Airway Smooth Muscle Cells
by Karosham Diren Reddy, Dikaia Xenaki, Ian M. Adcock, Brian G. G. Oliver and Razia Zakarya
Cells 2025, 14(1), 31; https://doi.org/10.3390/cells14010031 - 31 Dec 2024
Viewed by 822
Abstract
Background: Chronic obstructive pulmonary disease (COPD) is characterized by progressive and incurable airflow obstruction and chronic inflammation. Both TGF-β1 and CXCL8 have been well described as fundamental to COPD progression. DNA methylation and histone acetylation, which are well-understood epigenetic mechanisms regulating gene expression, [...] Read more.
Background: Chronic obstructive pulmonary disease (COPD) is characterized by progressive and incurable airflow obstruction and chronic inflammation. Both TGF-β1 and CXCL8 have been well described as fundamental to COPD progression. DNA methylation and histone acetylation, which are well-understood epigenetic mechanisms regulating gene expression, are associated with COPD progression. However, a deeper understanding of the complex mechanisms associated with DNA methylation, histone post-translational changes and RNA methylation in the context of regulatory pathways remains to be elucidated. We here report on how DNA methylation and histone acetylation inhibition differentially affect CXCL8 signaling in primary human non-COPD and COPD airway cells. Methods: Airway smooth muscle (ASM) cells, a pivotal cell type in COPD, were isolated from the small airways of heavy smokers with and without COPD. Histone acetylation and DNA methylation were inhibited before the TGF-β1 stimulation of cells. Subsequently, CXCL8 production and the abundance and activation of pertinent transcription regulatory proteins (NF-κB, p38 MAPK and JNK) were analyzed. Results: TGF-β1-stimulated CXCL8 release from ASM cells from ‘healthy’ smoker subjects was significantly modulated by DNA methylation (56.32 pg/mL and 56.60 pg/mL) and acetylation inhibitors (27.50 pg/mL and 48.85 pg/mL) at 24 and 48 h, respectively. However, modulation via the inhibition of DNA methylation (34.06 pg/mL and 43.18 pg/mL) and acetylation (23.14 pg/mL and 27.18 pg/mL) was observed to a lesser extent in COPD ASM cells. These changes were associated with differences in the TGF-β1 activation of NF-κB and MAPK pathways at 10 and 20 min. Conclusions: Our findings offer insight into differential epigenetics in controlling COPD ASM cells and provide a foundation warranting future studies on epigenetic differences associated with COPD diagnosis. This would provide a scope for developing therapeutic interventions targeting signaling and epigenetic pathways to improve patient outcomes. Full article
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15 pages, 4063 KiB  
Article
HDAC1 and HDAC2 Are Involved in Influenza A Virus-Induced Nuclear Translocation of Ectopically Expressed STAT3-GFP
by Jessica Leong and Matloob Husain
Viruses 2025, 17(1), 33; https://doi.org/10.3390/v17010033 - 29 Dec 2024
Viewed by 832
Abstract
Influenza A virus (IAV) remains a pandemic threat. Particularly, the evolution and increased interspecies and intercontinental transmission of avian IAV H5N1 subtype highlight the importance of continuously studying the IAV and identifying the determinants of its pathogenesis. Host innate antiviral response is the [...] Read more.
Influenza A virus (IAV) remains a pandemic threat. Particularly, the evolution and increased interspecies and intercontinental transmission of avian IAV H5N1 subtype highlight the importance of continuously studying the IAV and identifying the determinants of its pathogenesis. Host innate antiviral response is the first line of defense against IAV infection, and the transcription factor, the signal transducer and activator of transcription 3 (STAT3), has emerged as a critical component of this response. Also, histone deacetylase 1 (HDAC1) and HDAC2 have been identified as important components of IAV-induced host innate antiviral response. Upon IAV infection, STAT3 is activated and translocated to the nucleus to initiate the transcription of innate response genes. Also, the HDAC1 and HDAC2 are localized to the nucleus. In this study, we sought to investigate the role of HDAC1 and HDAC2 in IAV-induced STAT3 nuclear translocation. We employed a quantitative confocal microscopy approach and analyzed the nuclear translocation of plasmid-expressed STAT3-GFP in IAV-infected cells depleted with the expression of HDAC1 or HDAC2. We found that the depletion of both HDAC1 and HDAC2 expression inhibits the IAV-induced nuclear translocation of STAT3-GFP. These findings will help elucidate the significance of the emerging role of acetylation in IAV infection and disease severity. Full article
(This article belongs to the Special Issue Interplay Between Influenza Virus and Host Factors)
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24 pages, 696 KiB  
Review
Regulation of Histone Acetylation Modification on Biosynthesis of Secondary Metabolites in Fungi
by Xuwen Hou, Liyao Liu, Yu Li, Pengfei Wang, Xiaoqian Pan, Dan Xu, Daowan Lai and Ligang Zhou
Int. J. Mol. Sci. 2025, 26(1), 25; https://doi.org/10.3390/ijms26010025 - 24 Dec 2024
Cited by 2 | Viewed by 618
Abstract
The histone acetylation modification is a conservative post-translational epigenetic regulation in fungi. It includes acetylation and deacetylation at the lysine residues of histone, which are catalyzed by histone acetyltransferase (HAT) and deacetylase (HDAC), respectively. The histone acetylation modification plays crucial roles in fungal [...] Read more.
The histone acetylation modification is a conservative post-translational epigenetic regulation in fungi. It includes acetylation and deacetylation at the lysine residues of histone, which are catalyzed by histone acetyltransferase (HAT) and deacetylase (HDAC), respectively. The histone acetylation modification plays crucial roles in fungal growth and development, environmental stress response, secondary metabolite (SM) biosynthesis, and pathogenicity. One of the most important roles is to regulate the gene expression that is responsible for SM biosynthesis in fungi. This mini-review summarized the regulation of histone acetylation modification by HATs and HDACs on the biosynthesis of SMs in fungi. In most cases, histone acetylation by HATs positively regulated the biosynthesis of fungal SMs, while HDACs had their negative regulations. Some HATs and HDACs were revealed to regulate fungal SM biosynthesis. Hda1 was found to be the most efficient regulator to affect the biosynthesis of SMs in fungi. The regulated fungal species were mainly from the genera of Aspergillus, Calcarisporium, Cladosporium, Fusarium, Monascus, Penicillium, and Pestalotiopsis. With the strategy of histone acetylation modification, the biosynthesis of some harmful SMs will be inhibited, while the production of useful bioactive SMs will be promoted in fungi. The subsequent research should focus on the study of regulatory mechanisms. Full article
(This article belongs to the Section Molecular Microbiology)
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18 pages, 9775 KiB  
Article
Divergent Contribution of Cytoplasmic Actins to Nuclear Structure of Lung Cancer Cells
by Galina Shagieva, Vera Dugina, Anton Burakov, Yulia Levuschkina, Dmitry Kudlay, Sergei Boichuk, Natalia Khromova, Maria Vasileva and Pavel Kopnin
Int. J. Mol. Sci. 2024, 25(24), 13607; https://doi.org/10.3390/ijms252413607 - 19 Dec 2024
Viewed by 737
Abstract
A growing body of evidence suggests that actin plays a role in nuclear architecture, genome organisation, and regulation. Our study of human lung adenocarcinoma cells demonstrates that the equilibrium between actin isoforms affects the composition of the nuclear lamina, which in turn influences [...] Read more.
A growing body of evidence suggests that actin plays a role in nuclear architecture, genome organisation, and regulation. Our study of human lung adenocarcinoma cells demonstrates that the equilibrium between actin isoforms affects the composition of the nuclear lamina, which in turn influences nuclear stiffness and cellular behaviour. The downregulation of β-actin resulted in an increase in nuclear area, accompanied by a decrease in A-type lamins and an enhancement in lamin B2. In contrast, the suppression of γ-actin led to upregulation of the lamin A/B ratio through an increase in A-type lamins. Histone H3 post-translational modifications display distinct patterns in response to decreased actin isoform expression. The level of dimethylated H3K9me2 declined while acetylated H3K9ac increased in β-actin-depleted A549 cells. In contrast, the inhibition of γ-actin expression resulted in a reduction in H3K9ac. Based on our observations, we propose that β-actin plays a role in chromatin compaction and deactivation, and is involved in the elevation of nuclear stiffness through the control of the lamins ratio. The non-muscle γ-actin is presumably responsible for chromatin decondensation and activation. The identification of novel functions for actin isoforms offers insights into the mechanisms through which they influence cell fate during development and cancer progression. Full article
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