RESUMEN
Diet-induced obesity is associated with enhanced systemic inflammation that limits bone regeneration. HDAC inhibitors are currently being explored as anti-inflammatory agents. Prior reports show that myeloid progenitor-directed Hdac3 ablation enhances intramembranous bone healing in female mice. In this study, we determined if Hdac3 ablation increased intramembranous bone regeneration in mice fed a high-fat/high-sugar (HFD) diet. Micro-CT analyses demonstrated that HFD-feeding enhanced the formation of periosteal reaction tissue of control littermates, reflective of suboptimal bone healing. We confirmed enhanced bone volume within the defect of Hdac3-ablated females and showed that Hdac3 ablation reduced the amount of periosteal reaction tissue following HFD feeding. Osteoblasts cultured in a conditioned medium derived from Hdac3-ablated cells exhibited a four-fold increase in mineralization and enhanced osteogenic gene expression. We found that Hdac3 ablation elevated the secretion of several chemokines, including CCL2. We then confirmed that Hdac3 deficiency increased the expression of Ccl2. Lastly, we show that the proportion of CCL2-positve cells within bone defects was significantly higher in Hdac3-deficient mice and was further enhanced by HFD. Overall, our studies demonstrate that Hdac3 deletion enhances intramembranous bone healing in a setting of diet-induced obesity, possibly through increased production of CCL2 by macrophages within the defect.
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Dieta Occidental , Histona Desacetilasas , Osteogénesis , Animales , Femenino , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/deficiencia , Ratones , Dieta Occidental/efectos adversos , Osteoblastos/metabolismo , Dieta Alta en Grasa/efectos adversos , Periostio/metabolismo , Periostio/patología , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Regeneración Ósea , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/metabolismo , Obesidad/etiología , Obesidad/patologíaRESUMEN
The intrinsically disordered protein MeCP2 is a global transcriptional regulator encoded by the MECP2 gene. Although the structured domains of MeCP2 have been the subject of multiple studies, its unstructured regions have not been that extensively characterized. In this work, we show that MeCP2 possesses properties akin to those of supercharged proteins. By utilizing its unstructured portions, MeCP2 can successfully transduce across cell membranes and localize to heterochromatic foci in the nuclei, displaying uptake levels a third lower than a MeCP2 construct fused to the cell-penetrating peptide TAT. MeCP2 uptake can further be enhanced by the addition of compounds that promote endosomal escape following cellular trafficking by means of macropinocytosis. Using a combination of in silico prediction algorithms and live-cell imaging experiments, we mapped the sequence in MeCP2 responsible for its cellular incorporation, which bears a striking resemblance to TAT itself. Transduced MeCP2 was shown to interact with HDAC3. These findings provide valuable insight into the properties of MeCP2 and may be beneficial for devising future protein-based treatment strategies.
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Membrana Celular , Histona Desacetilasas , Proteína 2 de Unión a Metil-CpG , Proteína 2 de Unión a Metil-CpG/metabolismo , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/química , Humanos , Membrana Celular/metabolismo , Membrana Celular/química , Histona Desacetilasas/metabolismo , Histona Desacetilasas/química , Histona Desacetilasas/genética , Células HEK293 , Transporte de Proteínas , Péptidos de Penetración Celular/metabolismo , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/genéticaRESUMEN
Monacolin K (MK), also known as lovastatin, is a polyketide compound with the ability to reduce plasma cholesterol levels and many other bio-activities. Red yeast rice (also named Hongqu) rich in MK derived from Monascus fermentation has attracted widespread attention due to its excellent performance in reducing blood lipids. However, industrial Monascus fermentation suffers from the limitations such as low yield of MK, long fermentation period, and susceptibility to contamination. In this study, we firstly blocked the competitive pathway of MK biosynthesis to create polyketide synthase gene pigA (the key gene responsible for the biosynthesis of Monascus azaphilone pigments) deficient strain A1. Then, based on the strategies to increase precursor supply for MK biosynthesis, acetyl-CoA carboxylase gene acc overexpression strains C1 and C2 were constructed with WT and A1 as the parent, respectively. Finally, histone deacetylase gene hos2 overexpression strain H1 was constructed by perturbation of histone acetylation modification. HPLC detection revealed all these four strains significantly increased their abilities to produce MK. After 14 days of solid-state fermentation, the MK yields of strains A1, C1, C2, and H1 reached 2.03 g/100 g, 1.81 g/100 g, 2.45 g/100 g and 2.52 g/100 g, which increased by 28.5 %, 14.7 %, 43.9 % and 36.1 % compared to WT, respectively. RT-qPCR results showed that overexpression of hos2 significantly increased the expression level of almost all genes responsible for MK biosynthesis after 5-day growth. Overall, the abilities of these strains to produce MK has been greatly improved, and MK production period has been shortened to 14 days from 20 days, providing new approaches for efficient production of Hongqu rich in MK.
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Fermentación , Histonas , Lovastatina , Monascus , Monascus/metabolismo , Monascus/genética , Acetilación , Histonas/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Acetil-CoA Carboxilasa/genética , Sintasas Poliquetidas/genética , Sintasas Poliquetidas/metabolismo , Hipolipemiantes/farmacología , Productos Biológicos/metabolismo , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genéticaRESUMEN
Cell-cell junctions, and specifically desmosomes, are crucial for robust intercellular adhesion. Desmosomal function is compromised in the autoimmune blistering skin disease pemphigus vulgaris. We combine whole-genome knockout screening and a promotor screen of the desmosomal gene desmoglein 3 in human keratinocytes to identify novel regulators of intercellular adhesion. Kruppel-like-factor 5 (KLF5) directly binds to the desmoglein 3 regulatory region and promotes adhesion. Reduced levels of KLF5 in patient tissue indicate a role in pemphigus vulgaris. Autoantibody fractions from patients impair intercellular adhesion and reduce KLF5 levels in in vitro and in vivo disease models. These effects were dependent on increased activity of histone deacetylase 3, leading to transcriptional repression of KLF5. Inhibiting histone deacetylase 3 increases KLF5 levels and protects against the deleterious effects of autoantibodies in murine and human pemphigus vulgaris models. Together, KLF5 and histone deacetylase 3 are regulators of desmoglein 3 gene expression and intercellular adhesion and represent potential therapeutic targets in pemphigus vulgaris.
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Adhesión Celular , Desmogleína 3 , Queratinocitos , Factores de Transcripción de Tipo Kruppel , Pénfigo , Humanos , Pénfigo/metabolismo , Pénfigo/patología , Pénfigo/inmunología , Desmogleína 3/metabolismo , Desmogleína 3/genética , Animales , Queratinocitos/metabolismo , Ratones , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Autoanticuerpos/inmunología , Desmosomas/metabolismo , Modelos Animales de Enfermedad , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Regulación de la Expresión Génica , Regiones Promotoras Genéticas/genética , MasculinoRESUMEN
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) remains one of the most lethal urological malignancies even though a great number of improvements in diagnosis and management have achieved over the past few decades. Accumulated evidence revealed that histone deacetylases (HDACs) play vital role in cell proliferation, differentiation and apoptosis. Nevertheless, the biological functions of histone deacetylation modification related genes in ccRCC remains poorly understood. METHOD: Bulk transcriptomic data and clinical information of ccRCC patients were obtained from the TCGA database and collected from the Chinese PLA General Hospital. A total of 36 histone deacetylation genes were selected and studied in our research. Univariate cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, random forest (RF) analysis, and protein-protein interaction (PPI) network analysis were applied to identify key genes affecting the prognosis of ccRCC. The 'oncoPredict' algorithm was utilized for drug-sensitive analysis. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the potential biological function. The ssGSEA algorithm was used for tumor immune microenvironment analysis. The expression levels of HDAC10 were validated by RT-PCR and immunohistochemistry (IHC). 5-ethynyl-2'-deoxyuridine (EdU assay), CCK-8 assay, cell transwell migration and invasion assay and colony formation assay were performed to detect the proliferation and invasion ability of ccRCC cells. A nomogram incorporating HDAC10 and clinicopathological characteristics was established to predict the prognosis of ccRCC patients. RESULT: Two machine learning algorithms and PPI analysis identified four histone deacetylation genes that have a significant association with the prognosis of ccRCC, with HDAC10 being the key gene among them. HDAC10 is highly expressed in ccRCC and its high expression is associated with poor prognosis for ccRCC patients. Pathway enrichment and the experiments of EdU staining, CCK-8 assay, cell transwell migration and invasion assay and colony formation assay demonstrated that HDAC10 mediated the proliferation and metastasis of ccRCC cells and involved in reshaping the tumor microenvironment (TME) of ccRCC. A clinically reliable prognostic predictive model was established by incorporating HDAC10 and other clinicopathological characteristics ( https://nomogramhdac10.shinyapps.io/HDAC10_Nomogram/ ). CONCLUSION: Our study found the increased expression of HDAC10 was closely associated with poor prognosis of ccRCC patients. HDAC10 showed a pro-tumorigenic effect on ccRCC and promote the proliferation and metastasis of ccRCC, which may provide new light on targeted therapy for ccRCC.
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Carcinoma de Células Renales , Proliferación Celular , Histona Desacetilasas , Neoplasias Renales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Proliferación Celular/genética , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Pronóstico , Microambiente Tumoral/genética , Línea Celular Tumoral , Mapas de Interacción de Proteínas , Oncogenes/genética , AncianoRESUMEN
Diabetes mellitus (DM) is a well-documented risk factor of intervertebral disc degeneration (IVDD). The current study was aimed to clarify the effects and mechanisms of NADH: ubiquinone oxidoreductase subunit A3 (NDUFA3) in human nucleus pulposus cells (HNPCs) exposed to high glucose. NDUFA3 was overexpressed in HNPCs via lenti-virus transduction, which were co-treated with high glucose and rotenone (a mitochondrial complex I inhibitor) for 48 h. Cell activities were assessed for cell viability, cell apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) ratio, oxygen consumption rate (OCR) and mitochondrial complexes I activities. High glucose decreased cell viability, increased apoptotic cells, increased ROS production, decreased MMP levels and OCR values in HNPCs in a dose-dependent manner. Rotenone co-treatment augmented the high glucose-induced injuries on cell viability, apoptosis, ROS production and mitochondrial function. NDUFA3 overexpression counteracted the high glucose-induced injuries in HNPCs. HDAC/H3K27ac mechanism was involved in regulating NDUFA3 transcription. NDUFA3 knockdown decreased cell viability and increased apoptotic cells, which were reversed by ROS scavenger N-acetylcysteine. HDAC/H3K27ac-mediated transcription of NDUFA3 protects HNPCs against high glucose-induced injuries through suppressing cell apoptosis, eliminating ROS, improving mitochondrial function and oxidative phosphorylation. This study sheds light on candidate therapeutic targets and deepens the understanding of molecular mechanisms behind DM-induced IVDD.
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Apoptosis , Supervivencia Celular , Complejo I de Transporte de Electrón , Glucosa , Histonas , Mitocondrias , Núcleo Pulposo , Especies Reactivas de Oxígeno , Humanos , Glucosa/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Núcleo Pulposo/metabolismo , Núcleo Pulposo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Complejo I de Transporte de Electrón/genética , Histonas/metabolismo , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Rotenona/farmacología , Transcripción Genética/efectos de los fármacos , Células CultivadasRESUMEN
MAIN CONCLUSION: This review focuses on HATs and HDACs that modify non-histone proteins, summarizes functional mechanisms of non-histone acetylation as well as the roles of HATs and HDACs in rice and Arabidopsis. The growth and development of plants, as well as their responses to biotic and abiotic stresses, are governed by intricate gene and protein regulatory networks, in which epigenetic modifying enzymes play a crucial role. Histone lysine acetylation levels, modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), are well-studied in the realm of transcriptional regulation. However, the advent of advanced proteomics has unveiled that non-histone proteins also undergo acetylation, with its underlying mechanisms now being clarified. Indeed, non-histone acetylation influences protein functionality through diverse pathways, such as modulating protein stability, adjusting enzymatic activity, steering subcellular localization, influencing interactions with other post-translational modifications, and managing protein-protein and protein-DNA interactions. This review delves into the recent insights into the functional mechanisms of non-histone acetylation in plants. We also provide a summary of the roles of HATs and HDACs in rice and Arabidopsis, and explore their potential involvement in the regulation of non-histone proteins.
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Arabidopsis , Histona Acetiltransferasas , Histona Desacetilasas , Oryza , Proteínas de Plantas , Procesamiento Proteico-Postraduccional , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Acetilación , Oryza/genética , Oryza/metabolismo , Oryza/enzimología , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/enzimología , Histona Acetiltransferasas/metabolismo , Histona Acetiltransferasas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Regulación de la Expresión Génica de las Plantas , Histonas/metabolismoRESUMEN
ABSTRACT: Sepsis is a syndrome of systemic inflammatory response resulting from infection, which can lead to severe lung injury. Histone deacetylase 4 (HDAC4) is a key protein known to regulate a wide range of cellular processes. This study was designed to investigate the role of HDAC4 in lipopolysaccharide (LPS)-induced alveolar epithelial cell injury as well as to disclose its potential molecular mechanisms. The alveolar epithelial cell injury model was established by inducing A549 cells with LPS. A549 cell viability was detected by cell counting kit-8 assay and the transfection efficiency of small interfering RNA targeting HDAC4 was appraised utilizing Western blot. The levels of inflammatory cytokines and oxidative stress markers were detected using corresponding assay kits. Dichloro-dihydro-fluorescein diacetate assay was used for the measurement of reactive oxygen species (ROS) content. Flow cytometry, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolyl-carbocyanine iodide-1 staining, adenosine triphosphate (ATP) assay kits, and MitoSOX Red assay kits were employed to estimate cell apoptosis, mitochondrial membrane potential, ATP level, and mitochondrial ROS level, respectively. The oxygen consumption rate of A549 cells was evaluated with XF96 extracellular flux analyzer. Western blot was applied for the evaluation of HDAC4, apoptosis- and c-Jun N-terminal kinase (JNK)/activating protein-1 (AP-1) signaling pathway-related proteins. HDAC4 expression was found to be increased in LPS-induced A549 cells and HDAC4 silence inhibited inflammatory damage, repressed oxidative stress, alleviated cell apoptosis, improved mitochondrial function, and blocked JNK/AP-1 signaling in A549 cells stimulated by LPS, which were all reversed by JNK activator anisomycin. Collectively, the interference with HDAC4 could ameliorate LPS-induced alveolar epithelial cell injury, and such protective effect may be potentially mediated through the JNK/AP-1 signaling pathway.
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Células Epiteliales Alveolares , Histona Desacetilasas , Lipopolisacáridos , Sepsis , Humanos , Células A549 , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Sepsis/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Transcripción AP-1/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Apoptosis/efectos de los fármacos , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Heterochromatin enforces transcriptional gene silencing and can be epigenetically inherited, but the underlying mechanisms remain unclear. Here, we show that histone deacetylation, a conserved feature of heterochromatin domains, blocks SWI/SNF subfamily remodelers involved in chromatin unraveling, thereby stabilizing modified nucleosomes that preserve gene silencing. Histone hyperacetylation, resulting from either the loss of histone deacetylase (HDAC) activity or the direct targeting of a histone acetyltransferase to heterochromatin, permits remodeler access, leading to silencing defects. The requirement for HDAC in heterochromatin silencing can be bypassed by impeding SWI/SNF activity. Highlighting the crucial role of remodelers, merely targeting SWI/SNF to heterochromatin, even in cells with functional HDAC, increases nucleosome turnover, causing defective gene silencing and compromised epigenetic inheritance. This study elucidates a fundamental mechanism whereby histone hypoacetylation, maintained by high HDAC levels in heterochromatic regions, ensures stable gene silencing and epigenetic inheritance, providing insights into genome regulatory mechanisms relevant to human diseases.
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Ensamble y Desensamble de Cromatina , Epigénesis Genética , Silenciador del Gen , Heterocromatina , Histona Desacetilasas , Histonas , Nucleosomas , Heterocromatina/metabolismo , Heterocromatina/genética , Nucleosomas/metabolismo , Nucleosomas/genética , Histonas/metabolismo , Histonas/genética , Acetilación , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Humanos , Histona Acetiltransferasas/metabolismo , Histona Acetiltransferasas/genética , AnimalesRESUMEN
Infertility caused by lipopolysaccharide (LPS) exposure due to infection is endangering male fertility worldwide, but the mechanism remains unclear. The blood-testis barrier (BTB) is essential for maintaining spermatogenesis and male fertility. In the present study, we showed that LPS (5.0 mg/kg) treatment markedly down-regulated the expression of BTB-related proteins, expanded the biotin penetration distance and caused histopathological injury in seminiferous tubules in mouse testes. Notably, testicular macrophage M1 polarization induced by LPS seems to be related to BTB damage, which was well confirmed by co-culture of RAW264.7 and TM4 cells in vitro. Interestingly, a low-dose LPS (0.1 mg/kg) pretreatment attenuated down-regulation of BTB-related proteins expression and histopathological injury and shorten biotin penetration distance in seminiferous tubules caused by LPS. Correspondingly, a low-dose LPS pretreatment suppresses testicular macrophage M1 polarization induced by LPS in mouse testes. Further experiments revealed that histone deacetylase 5 (HDAC5) was markedly down-regulated at 2 h and slightly down-regulated at 8 h, but up-regulated at 24 h in mouse testes after LPS treatment. Additionally, low-dose LPS pretreatment against the down-regulation of HDAC5 protein caused by LPS treatment. Notably, the suppressed testicular macrophage M1 polarization by low-dose LPS pretreatment was broken by BRD4354, a specific inhibitor of HDAC5 in vitro. These results suggest suppressed testicular macrophage M1 polarization by HDAC5 enforces insensitivity to LPS-elicited BTB damage.
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Barrera Hematotesticular , Histona Desacetilasas , Lipopolisacáridos , Macrófagos , Animales , Masculino , Lipopolisacáridos/toxicidad , Barrera Hematotesticular/efectos de los fármacos , Ratones , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Testículo/efectos de los fármacos , Testículo/metabolismo , Células RAW 264.7RESUMEN
The metastasis-associated protein (MTA) family plays a crucial role in the development of breast cancer, a common malignancy with a high incidence rate among women. However, the mechanism by which each member of the MTA family contributes to breast cancer progression is poorly understood. In this study, we aimed to investigate the roles of MTA1, MTA3, and tripartite motif-containing 21 (TRIM21) in the proliferation, invasion, epithelial-mesenchymal transition (EMT), and stem cell-like properties of breast cancer cells in vivo and in vitro. The molecular mechanisms of the feedback loop between MTA1 and MTA3/TRIM21 regulated by estrogen were explored using Chromatin immunoprecipitation (ChIP), luciferase reporter, immunoprecipitation (IP), and ubiquitination assays. These findings demonstrated that MTA1 acts as a driver to promote the progression of breast cancer by repressing the transcription of tumor suppressor genes, including TRIM21 and MTA3. Conversely, MTA3 inhibited MTA1 transcription and TRIM21 regulated MTA1 protein stability in breast cancer. Estrogen disrupted the balance between MTA1 and MTA3, as well as between MTA1 and TRIM21, thereby affecting stemness and the EMT processes in breast cancer. These findings suggest that MTA1 plays a vital role in stem cell fate and the hierarchical regulatory network of EMT through negative feedback loops with MTA3 or TRIM21 in response to estrogen, supporting MTA1, MTA3, and TRIM21 as potential prognostic biomarkers and MTA1 as a treatment target for future breast cancer therapies.
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Neoplasias de la Mama , Transición Epitelial-Mesenquimal , Estrógenos , Histona Desacetilasas , Células Madre Neoplásicas , Proteínas Represoras , Transactivadores , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Transactivadores/metabolismo , Transactivadores/genética , Estrógenos/farmacología , Estrógenos/metabolismo , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Animales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Retroalimentación Fisiológica/efectos de los fármacos , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Ratones Desnudos , Células MCF-7 , Ratones Endogámicos BALB C , Proteínas de NeoplasiasRESUMEN
Epigenetics involves reversible modifications in gene expression without altering the genetic code itself. Among these modifications, histone deacetylases (HDACs) play a key role by removing acetyl groups from lysine residues on histones. Overexpression of HDACs is linked to the proliferation and survival of tumor cells. To combat this, HDAC inhibitors (HDACi) are commonly used in cancer treatments. However, pan-HDAC inhibition can lead to numerous side effects. Therefore, isoform-selective HDAC inhibitors, such as HDAC3i, could be advantageous for treating various medical conditions while minimizing off-target effects. To date, computational approaches that use only the SMILES notation without any experimental evidence have become increasingly popular and necessary for the initial discovery of novel potential therapeutic drugs. In this study, we develop an innovative and high-precision stacked-ensemble framework, called Stack-HDAC3i, which can directly identify HDAC3i using only the SMILES notation. Using an up-to-date benchmark dataset, we first employed both molecular descriptors and Mol2Vec embeddings to generate feature representations that cover multi-view information embedded in HDAC3i, such as structural and contextual information. Subsequently, these feature representations were used to train baseline models using nine popular ML algorithms. Finally, the probabilistic features derived from the selected baseline models were fused to construct the final stacked model. Both cross-validation and independent tests showed that Stack-HDAC3i is a high-accuracy prediction model with great generalization ability for identifying HDAC3i. Furthermore, in the independent test, Stack-HDAC3i achieved an accuracy of 0.926 and Matthew's correlation coefficient of 0.850, which are 0.44-6.11% and 0.83-11.90% higher than its constituent baseline models, respectively.
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Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/química , Humanos , Aprendizaje Automático , Descubrimiento de Drogas/métodosRESUMEN
Diffuse midline gliomas (DMGs) are aggressive and fatal pediatric tumors of the central nervous system that are highly resistant to treatments. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor growth reduction in mice treated with the drug combination. These results highlight the combined treatment with PIN1 and HDAC inhibitors as a promising therapeutic approach for these aggressive tumors.
Diffuse midline gliomas (DMGs) are among the most aggressive and fatal brain cancers in children. They are often associated with changes in histones, the proteins that control gene activity and give chromosomes their structure. Most children with DMGs, for example, share the same anomaly in their histone H3 protein (referred to as the H3-K27M mutation). This change affects how small chemical tags called methyl and acetyl groups can be added onto histone 3, which in turn alters the way the protein can switch genes on and off. As a result, tumours start to develop. One potential therapeutic strategy against DMGs is to use histone deacetylase inhibitors (HDACi), a promising type of drugs which inhibits the enzymes that remove acetyl groups from histones. Patients can develop resistance to HDACi, however, highlighting the need to explore other approaches. One possibility is to treat patients with several types of drugs, each usually targeting a distinct biological process that contributes to the emergence of cancer. This combined approach can have multiple benefits; the drugs potentially amplify each other's effect, for example, and it is also less likely for cells to become resistant to more than one compound at the time. In addition, each drug in the combination can be used in a lower dose to reduce side effects and benefit patients. DMG tumour cells often feature higher activity levels of a protein known as MYC, which can contribute to the growth of the tumour. Algranati, Oren et al. therefore set out to test whether combining an HDACi known as Vorinostat with a drug that blocks MYC activity (Sulfopin) can act as an effective treatment for this cancer. Tumour samples from eight DMG patients were treated with either Sulfopin alone, or Sulfopin in association with Vorinostat. Cells exposed to both drugs were less likely to survive, and additional genetic experiments showed that the combined treatment had resulted in pathways that promote tumour development being blocked. When both Sulfopin and Vorinostat were administered to mice made to grow human DMG tumors, the animals showed a greater reduction in tumor growth. Treatment options for DMG are usually limited, with chemotherapy often being ineffective and surgery impossible. The work by Algranati, Oren et al. suggests that combining HDACi and drugs targeting the MYC pathway is a strategy that should be examined further to determine whether clinical applications are possible.
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Glioma , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Histonas , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/patología , Humanos , Animales , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Histonas/metabolismo , Histonas/genética , Inhibidores de Histona Desacetilasas/farmacología , Ratones , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Vorinostat/farmacología , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral , Niño , Modelos Animales de Enfermedad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Nuclear factor E2-related factor 2 (Nrf2), a redox-sensitive transcription factor, regulates proangiogenic mediators, and antioxidant and detoxification enzymes. However, hitherto its regulation in the progression of DFU was poorly examined. The regulation of Nrf2 has been reported to be affected by various factors, including histone deacetylase (HDACs) and DNA methylation. The present study aimed to profile all classes of HDACs and correlate them with Nrf2 and angiogenic markers in the tissue biopsies of different grades of DFU patients (n = 20 in each grade). The gene expression profile of Nrf2 and its downstream targets, angiogenic markers, and all classes of HDACs were assessed using qPCR. Spearman's correlation was performed to analyze the correlation of HDACs with Nrf2 and its downstream targets along with angiogenic markers. We observed a progressive decrease in the gene expression of Nrf2 and angiogenic markers such as VEGF, HIF-1α, and SDF-1α and also an increase in the TSP-2 expression in different grades of DFU. In parallel, a significant downregulation of HDAC2/8 and SIRT1/2/4 has been observed in various grades of DFU subjects. On the other hand, HDAC1/3/4/11 and SIRT3/5/6/7 showed upregulation in different grades of DFU and the maximum increase was observed in Grade 3 patients. A significant negative correlation between Nrf2 and HDAC4, angiogenic markers, and HDAC4 suggested the pivotal role of the HDAC4-regulated Nrf2-mediated angiogenesis among DFU subjects. We have generated a first line of evidence on the epigenetic regulation of Nrf2 and its correlation with angiogenesis in the progression of diabetic foot ulcers.
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Pie Diabético , Progresión de la Enfermedad , Epigénesis Genética , Histona Desacetilasas , Factor 2 Relacionado con NF-E2 , Neovascularización Patológica , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Pie Diabético/metabolismo , Pie Diabético/genética , Pie Diabético/patología , Masculino , Neovascularización Patológica/metabolismo , Neovascularización Patológica/genética , Persona de Mediana Edad , Femenino , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Trombospondinas/metabolismo , Trombospondinas/genética , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/genética , Anciano , AngiogénesisRESUMEN
Insect developmental transitions are precisely coordinated by ecdysone and juvenile hormone (JH). We previously revealed that accumulated H3K27 trimethylation (H3K27me3) at the locus encoding JH signal transducer Hairy is involved in the larval-pupal transition in insects, but the underlying mechanism remains to be fully defined. Here, we show in Drosophila and Bombyx that Rpd3-mediated H3K27 deacetylation in the prothoracic gland during the last larval instar promotes ecdysone biosynthesis and the larval-pupal transition by enabling H3K27me3 accumulation at the Hairy locus to induce its transcriptional repression. Importantly, we find that the homeodomain transcription factor Schlank acts to switch active H3K27 acetylation (H3K27ac) to repressive H3K27me3 at the Hairy locus by directly binding to the Hairy promoter and then recruiting the histone deacetylase Rpd3 and the histone methyltransferase PRC2 component Su(z)12 through physical interactions. Moreover, Schlank inhibits Hairy transcription to facilitate the larval-pupal transition, and the Schlank signaling cascade is suppressed by JH but regulated in a positive feedback manner by ecdysone. Together, our data uncover that Schlank mediates epigenetic reprogramming of H3K27 modifications in hormone actions during insect developmental transition.
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Proteínas de Drosophila , Ecdisona , Regulación del Desarrollo de la Expresión Génica , Histonas , Larva , Animales , Histonas/metabolismo , Acetilación , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Ecdisona/metabolismo , Larva/metabolismo , Larva/crecimiento & desarrollo , Larva/genética , Bombyx/metabolismo , Bombyx/genética , Bombyx/crecimiento & desarrollo , Hormonas Juveniles/metabolismo , Metilación , Drosophila melanogaster/metabolismo , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/genética , Transducción de Señal , Pupa/metabolismo , Pupa/crecimiento & desarrollo , Pupa/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Proteínas de Insectos/metabolismo , Proteínas de Insectos/genética , Proteínas Represoras , Factores de Transcripción con Motivo Hélice-Asa-Hélice BásicoRESUMEN
BACKGROUND: Oesophageal cancer remains a challenging disease with high mortality rates and few therapeutic options. In view of these difficulties, epigenetic drugs have emerged as potential alternatives for patient care. The goal of this study was to evaluate the effect and biological consequences of Panobinostat treatment, an HDAC (histone deacetylase) inhibitor already approved for treatment of patients with multiple myeloma, in oesophageal cell lines of normal and malignant origin, with the latter being representative of the two main histological subtypes: adenocarcinoma and squamous cell carcinoma. RESULTS: Panobinostat treatment inhibited growth and hindered proliferation, colony formation and invasion of oesophageal cancer cells. Considering HDAC tissue expression, HDAC1 was significantly upregulated in normal oesophageal epithelium in comparison with tumour tissue, whereas HDAC3 was overexpressed in oesophageal cancer compared to non-malignant mucosa. No differences between normal and tumour tissue were observed for HDAC2 and HDAC8 expression. CONCLUSIONS: Panobinostat exposure effectively impaired malignant features of oesophageal cancer cells. Because HDAC3 was shown to be overexpressed in oesophageal tumour samples, this epigenetic drug may represent an alternative therapeutic option for oesophageal cancer patients.
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Adenocarcinoma , Carcinoma de Células Escamosas , Proliferación Celular , Neoplasias Esofágicas , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Panobinostat , Humanos , Panobinostat/farmacología , Panobinostat/uso terapéutico , Panobinostat/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Línea Celular Tumoral , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Proliferación Celular/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasa 1/genética , Histona Desacetilasa 2/genética , Proteínas Represoras/genética , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Indoles/farmacología , Indoles/uso terapéutico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patologíaRESUMEN
Exposure to particulate matter (PM) can cause airway inflammation and worsen various airway diseases. However, the underlying molecular mechanism by which PM triggers airway inflammation has not been completely elucidated, and effective interventions are lacking. Our study revealed that PM exposure increased the expression of histone deacetylase 9 (HDAC9) in human bronchial epithelial cells and mouse airway epithelium through the METTL3/m6A methylation/IGF2BP3 pathway. Functional assays showed that HDAC9 upregulation promoted PM-induced airway inflammation and activation of MAPK signaling pathway in vitro and in vivo. Mechanistically, HDAC9 modulated the deacetylation of histone 4 acetylation at K12 (H4K12) in the promoter region of dual specificity phosphatase 9 (DUSP9) to repress the expression of DUSP9 and resulting in the activation of MAPK signaling pathway, thereby promoting PM-induced airway inflammation. Additionally, HDAC9 bound to MEF2A to weaken its anti-inflammatory effect on PM-induced airway inflammation. Then, we developed a novel inhaled lipid nanoparticle system for delivering HDAC9 siRNA to the airway, offering an effective treatment for PM-induced airway inflammation. Collectively, we elucidated the crucial regulatory mechanism of HDAC9 in PM-induced airway inflammation and introduced an inhaled therapeutic approach targeting HDAC9. These findings contribute to alleviating the burden of various airway diseases caused by PM exposure.
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Epigénesis Genética , Histona Desacetilasas , Material Particulado , Regulación hacia Arriba , Animales , Material Particulado/toxicidad , Humanos , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Epigénesis Genética/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Ratones , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Inflamación , Nanopartículas/química , Nanopartículas/toxicidad , Ratones Endogámicos C57BL , Línea Celular , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , MasculinoRESUMEN
Emerging preclinical autism research has shown the therapeutic promise of pharmacological inhibitors for epigenetic enzymes, such as histone deacetylases (HDAC), euchromatic histone methyltransferases (EHMT), and lysine-specific histone demethylase 1A (LSD1). These interventions restore gene expression, synaptic function, and behavioral performance in autism models, highlighting a new strategy for autism treatment.
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Trastorno Autístico , Epigénesis Genética , Histona Demetilasas , Humanos , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/genética , Animales , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genéticaRESUMEN
Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for various developmental and physiological functions. Although its dysfunction is increasingly recognized in abnormal phenotypes, to our knowledge, there have been no established reports of human diseases directly linked to HDAC3 dysfunction. Using trio exome sequencing and extensive phenotypic analysis, we correlated heterozygous de novo variants in HDAC3 with a neurodevelopmental disorder having variable clinical presentations, frequently associated with intellectual disability, developmental delay, epilepsy, and musculoskeletal abnormalities. In a cohort of six individuals, we identified missense variants in HDAC3 (c.277G>A [p.Asp93Asn], c.328G>A [p.Ala110Thr], c.601C>T [p.Pro201Ser], c. 797T>C [p.Leu266Ser], c.799G>A [p.Gly267Ser], and c.1075C>T [p.Arg359Cys]), all located in evolutionarily conserved sites and confirmed as de novo. Experimental studies identified defective deacetylation activity in the p.Asp93Asn, p.Pro201Ser, p.Leu266Ser, and p.Gly267Ser variants, positioned near the enzymatic pocket. In addition, proteomic analysis employing co-immunoprecipitation revealed that the disrupted interactions with molecules involved in the CoREST and NCoR complexes, particularly in the p.Ala110Thr variant, consist of a central pathogenic mechanism. Moreover, immunofluorescence analysis showed diminished nuclear to cytoplasmic fluorescence ratio in the p.Ala110Thr, p.Gly267Ser, and p.Arg359Cys variants, indicating impaired nuclear localization. Taken together, our study highlights that de novo missense variants in HDAC3 are associated with a broad spectrum of neurodevelopmental disorders, which emphasizes the complex role of HDAC3 in histone deacetylase activity, multi-protein complex interactions, and nuclear localization for proper physiological functions. These insights open new avenues for understanding the molecular mechanisms of HDAC3-related disorders and may inform future therapeutic strategies.
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Epigénesis Genética , Histona Desacetilasas , Mutación Missense , Trastornos del Neurodesarrollo , Humanos , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Mutación Missense/genética , Trastornos del Neurodesarrollo/genética , Masculino , Femenino , Preescolar , Niño , Discapacidad Intelectual/genética , Secuenciación del Exoma , Adolescente , Discapacidades del Desarrollo/genética , Fenotipo , Lactante , Co-Represor 1 de Receptor Nuclear/genética , Co-Represor 1 de Receptor Nuclear/metabolismoRESUMEN
Post-stroke anxiety (PSA) seriously affects the prognosis of patients, which is an urgent clinical problem to be addressed. However, the pathological mechanism of PSA is largely unclear. Here, we found that neuronal HIPK2 expression was upregulated in the ischemic lesion after stroke. The upregulation of HIPK2 promotes Drp1 oligomerization through the HDAC3-dependent pathway, leading to excessive mitochondrial damage. This subsequently triggers the release of cellular cytokines such as IL-18 from neurons under ischemic stress. Microglia are capable of responding to IL-18, which promotes their activation and enhances their phagocytosis, ultimately resulting in the loss of synapses and neurons, thereby exacerbating the pathological progression of PSA. HIPK2 knockdown or inhibition suppresses excessive pruning of neuronal synapses by activated microglia in the contralateral vCA1 region to compromise inactivated anxiolytic pBLA-vCA1Calb1+ circuit, relieving anxiety-like behavior after stroke. Furthermore, we discovered that early remimazolam administration can remodel HIPK2-HDAC3 axis, ameliorating the progression of PSA. In conclusion, our study revealed that the neuronal HIPK2-HDAC3 axis in the ischemic focus regulates mitochondrial fragmentation to balance inflammation stress reservoir to participate in anxiety susceptibility after stroke.