Histone Acetylation Modification Research Articles

Effective enhancement of the ability of Monascus pilosus to produce lipid-lowering compound Monacolin K via perturbation of metabolic flux and histone acetylation modification

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.

Histone acetylation regulated by histone deacetylases during spermatogenesis.

Physical, chemical, and biological factors in the environment constantly influence in vivo and in vitro biological processes, including diverse histone modifications involved in cancer and metabolism. However, the intricate mechanisms of acetylation regulation remain poorly elucidated. In mammalian spermatogenesis, acetylation plays a crucial role in repairing double-strand DNA breaks, regulating gene transcription, and modulating various signaling pathways. This review summarizes the histone acetylation sites in the mouse testis and provides a comprehensive overview of how histone acetylation is involved in different stages of spermatogenesis under the regulation by histone deacetylases. The regulatory functions of various class histone deacetylases during spermatogenesis and the crossroad between histone acetylation and other histone modifications are highlighted. It is imperative to understand the mechanisms of histone acetylation regulated by histone deacetylases in spermatogenesis, which facilitates to prevent and treat infertility-related diseases.

Electroacupuncture ameliorates blood-brain barrier disruption after ischemic stroke through histone acetylation regulation at the matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 2 genes.

To explore whether the regulation of matrix metalloproteinase 9 (MMP-9)/ tissue inhibitors of MMPs (TIMPs) gene expression through histone acetylation is a possible mechanism by which electroacupuncture (EA) protects blood-brain barrier (BBB) integrity in a middle cerebral artery occlusion (MCAO) rat model. Male Sprague-Dawley rats were divided into four groups: the sham group, the MCAO group, the MCAO + EA (MEA) group, and the MCAO + EA + HAT inhibitor (HATi) group. The MCAO model was generated by blocking the middle cerebral artery. EA was applied to Baihui (GV20). Samples were collected 1 or 3 d after reperfusion. Neurological function scores and Evans blue extravasation were employed to evaluate the poststroke injury. The effect of EA on MMP-9/TIMPs gene expression was assessed by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and chromatin immunoprecipitation (ChIP). Our results showed that EA treatment prominently improved neurological function and ameliorated BBB disruption. The RT-qPCR assay showed that EA reduced the expression of MMP-9 and promoted TIMP-2 mRNA expression, but HATi reversed these effects of EA. In addition, ChIP results revealed that EA decreased the enrichment of H3K9ace/H3K27ace at MMP-9 promoters and notably stimulated the recruitment of H3K9ace/H3K27ace at TIMP-2 promoter. EA treatment at Baihui (GV20) regulates the transcription of MMP-9 and TIMP-2 through histone acetylation modification in the acute stage of stroke, which preserves the structural integrity of the BBB in MCAO rats. These findings suggested that the histone acetylation-mediated transcriptional activity of target genes may be a crucial mechanism of EA treatment in stroke.

Epigenetic markers of tooth eruption - DNA methylation and histone acetylation.

The present study aimed to evaluate whether epigenetic markers are expressed in the dental follicles surrounding ectopically erupting teeth. Twenty-one dental follicles were collected in 20 adolescent children through surgical exposure of ectopic teeth. The epigenetic modifications of DNA methylation and histone acetylation were evaluated by immunohistochemistry. The results showed cells positive for DNA-methyltransferase 1 (DNMT1), DNA methyltransferase 3 beta (DNMT3B), ten-eleven translocation-2 (TET2), acetyl-histone H3 (AcH3), acetyl-histone H4 (AcH4), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC) were present in all the samples. The levels of epigenetic markers representing active chromatin (5hmC, AcH3, AcH4, and TET2) were statistically significantly higher than those of markers representing inactive chromatin (5mC, DNMT3B, DNMT1). In conclusion, follicles in ectopic teeth display major epigenetic modifications. In the follicles, epigenetic markers associated with the activation of bone-related genes are more abundant than markers associated with the inactivation of bone-related genes.

Influenza Vaccination Mediates SARS-CoV-2 Spike Protein Peptide-Induced Inflammatory Response via Modification of Histone Acetylation.

The effectiveness of coronavirus disease 2019 (COVID-19) vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain rapidly wanes over time. Growing evidence from epidemiological studies suggests that influenza vaccination is associated with a reduction in the risk of SARS-CoV-2 infection and COVID-19 severity. However, the underlying mechanisms remain elusive. Here, we investigate the cross-reactive immune responses of influenza vaccination to SARS-CoV-2 spike protein peptides based on in vitro study. Our data indicate enhanced activation-induced-marker (AIM) expression on CD4+ T cells in influenza-vaccination (IV)-treated peripheral blood mononuclear cells (PBMCs) upon stimulation with spike-protein-peptide pools. The fractions of other immune cell subtypes, including CD8+ T cells, monocytes, NK cells, and antigen-presenting cells, were not changed between IV-treated and control PBMCs following ex vivo spike-protein-peptide stimulation. However, the classical antiviral (IFN-γ) and anti-inflammatory (IL-1RA) cytokine responses to spike-protein-peptide stimulation were still enhanced in PBMCs from both IV-immunized adult and aged mice. Decreased expression of proinflammatory IL-1β, IL-12p40, and TNF-α is associated with inhibited levels of histone acetylation in PBMCs from IV-treated mice. Remarkably, prior immunity to SARS-CoV-2 does not result in modification of histone acetylation or hemagglutinin-protein-induced cytokine responses. This response is antibody-independent but can be mediated by manipulating the histone acetylation of PBMCs. These data experimentally support that influenza vaccination could induce modification of histone acetylation in immune cells and reveal the existence of potential cross-reactive immunity to SARS-CoV-2 antigens, which may provide insights for the adjuvant of influenza vaccine to limit COVID-19-related inflammatory responses.

SNORA28 Promotes Proliferation and Radioresistance in Colorectal Cancer Cells through the STAT3 Pathway by Increasing H3K9 Acetylation in the LIFR Promoter.

Radiotherapy is essential for treating colorectal cancer (CRC), especially in advanced rectal cancer. However, the low radiosensitivity of CRC cells greatly limits radiotherapy efficacy. Small nucleolar RNAs (snoRNAs) are a class of noncoding RNA that primarily direct post-transcriptional modifications of ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and other cellular RNAs. While snoRNAs are involved in tumor progression and chemoresistance, their association with radiosensitivity remains largely unknown. Herein, SNORA28 is shown highly expressed in CRC and is positively associated with poor prognosis. Furthermore, SNORA28 overexpression enhances the growth and radioresistance of CRC cells in vitro and in vivo. Mechanistically, SNORA28 acts as a molecular decoy that recruits bromodomain-containing protein 4 (BRD4), which increases the level of H3K9 acetylation at the LIFR promoter region. This stimulates LIFR transcription, which in turn triggers the JAK1/STAT3 pathway, enhancing the proliferation and radioresistance of CRC cells. Overall, these results highlight the ability of snoRNAs to regulate radiosensitivity in tumor cells and affect histone acetylation modification in the promoter region of target genes, thus broadening the current knowledge of snoRNA biological functions and the mechanism underlying target gene regulation.

SANT proteins modulate gene expression by coordinating histone H3KAc and Khib levels and regulate plant heat tolerance.

Histone post-translational modifications (PTMs), such as acetylation and recently identified lysine 2-hydroxyisobutyrylation (Khib), act as active epigenomic marks in plants. SANT domain-containing proteins SANT1, SANT2, SANT3 and SANT4 (SANT1/2/3/4), derived from PIF/Harbinger transposases, form a complex with HISTONE DEACETYLASE 6 (HDA6) to regulate gene expression via histone deacetylation. However, whether SANT1/2/3/4 coordinate different types of PTMs to regulate transcription and mediate responses to specific stresses in plants remains unclear. Here, in addition to modulating histone deacetylation, we found that SANT1/2/3/4 proteins acted like HDA6 or HDA9 in regulating the removal of histone Khib in Arabidopsis (Arabidopsis thaliana). Histone H3 lysine acetylation (H3KAc) and histone Khib were coordinated by SANT1/2/3/4 to regulate gene expression, with H3KAc playing a predominant role and Khib acting complementarily to H3KAc. SANT1/2/3/4 mutation significantly increased the expression of heat-inducible genes with concurrent change of H3KAc levels under normal and heat stress conditions, resulting in enhanced thermotolerance. This study revealed the critical roles of Harbinger transposon-derived SANT domain-containing proteins in transcriptional regulation by coordinating different types of histone PTMs and in the regulation of plant thermotolerance by mediating histone acetylation modification.

Modulation of histone acetylation enables fully mechanized hybrid rice breeding.

Hybrid rice has achieved high grain yield and greatly contributes to food security, but the manual-labour-intensive hybrid seed production process limits fully mechanized hybrid rice breeding. For next-generation hybrid seed production, the use of small-grain male sterile lines to mechanically separate small hybrid seeds from mixed harvest is promising. However, it is difficult to find ideal grain-size genes for breeding ideal small-grain male sterile lines without penalties in the number of hybrid seeds and hybrid rice yield. Here we report that the use of small-grain alleles of the ideal grain-size gene GSE3 in male sterile lines enables fully mechanized hybrid seed production and dramatically increases hybrid seed number in three-line and two-line hybrid rice systems. The GSE3 gene encodes a histone acetyltransferase that binds histones and influences histone acetylation levels. GSE3 is recruited by the transcription factor GS2 to the promoters of their co-regulated grain-size genes and influences the histone acetylation status of their co-regulated genes. Field trials demonstrate that genome editing of GSE3 can be used to immediately improve current elite male sterile lines of hybrid rice for fully mechanized hybrid rice breeding, providing a new perspective for mechanized hybrid breeding in other crops.

Pomiferin targeting SLC9A9 based on histone acetylation modification pattern is a potential therapeutical option for gastric cancer with high malignancy

Changes in histone acetylation status are associated with gastric cancer (GC) progression. Pomiferin is a natural flavonoid, however, the specific role of pomiferin in the treatment of GC is still unclear, and its targets are not well clarified. In this work, the prognostic genes related with histone acetylation in GC were screened by univariate Cox analysis. Next, a risk model of was constructed using least absolute shrinkage and selection operator-Cox regression analyses, and multivariate Cox analysis was used for identifying the independent risk factor. Molecular docking was performed using AutoDock Vina to validate the interaction between solute carrier family 9 member A9 (SLC9A9) and pomiferin. In vitro and in vivo models were applied to investigate the tumor-suppressive role of pomiferin against GC. The inhibitory effects of pomiferin on EGFR/PI3K/AKT signaling were valdiated by Western blotting, immunofluorescence staining and qPCR. Here, a prognostic risk model based on histone acetylation regulators was established, and SLC9A9 was identified as a risk factor associated with histone acetylation status in GC. SLC9A9 expression was associated with abnormal immune microenvironment of tumor. Pomiferin had a high binding affinity with SLC9A9, and both pomiferin treatment and depletion of SLC9A9 repressed the malignant phenotypes of GC cells. Mechanistically, pomiferin inactivates EGFR/PI3K/AKT signaling in GC cells. In summary, SLC9A9, as a indicator of abnormal histone acetylation status of GC, functions as an oncogenic factor. Pomiferin binds with SLC9A9 to inactivate EGFR/PI3K/AKT pathway, to block GC progression, suggesting it is a promising drug for the patients with highly malignant GC.

KAT8 beyond Acetylation: A Survey of Its Epigenetic Regulation, Genetic Variability, and Implications for Human Health.

Lysine acetyltransferase 8, also known as KAT8, is an enzyme involved in epigenetic regulation, primarily recognized for its ability to modulate histone acetylation. This review presents an overview of KAT8, emphasizing its biological functions, which impact many cellular processes and range from chromatin remodeling to genetic and epigenetic regulation. In many model systems, KAT8's acetylation of histone H4 lysine 16 (H4K16) is critical for chromatin structure modification, which influences gene expression, cell proliferation, differentiation, and apoptosis. Furthermore, this review summarizes the observed genetic variability within the KAT8 gene, underscoring the implications of various single nucleotide polymorphisms (SNPs) that affect its functional efficacy and are linked to diverse phenotypic outcomes, ranging from metabolic traits to neurological disorders. Advanced insights into the structural biology of KAT8 reveal its interaction with multiprotein assemblies, such as the male-specific lethal (MSL) and non-specific lethal (NSL) complexes, which regulate a wide range of transcriptional activities and developmental functions. Additionally, this review focuses on KAT8's roles in cellular homeostasis, stem cell identity, DNA damage repair, and immune response, highlighting its potential as a therapeutic target. The implications of KAT8 in health and disease, as evidenced by recent studies, affirm its importance in cellular physiology and human pathology.

Activation of secondary metabolite gene clusters in Chaetomium olivaceum via the deletion of a histone deacetylase

Histone acetylation modifications in filamentous fungi play a crucial role in epigenetic gene regulation and are closely linked to the transcription of secondary metabolite (SM) biosynthetic gene clusters (BGCs). Histone deacetylases (HDACs) play a pivotal role in determining the extent of histone acetylation modifications and act as triggers for the expression activity of target BGCs. The genus Chaetomium is widely recognized as a rich source of novel and bioactive SMs. Deletion of a class I HDAC gene of Chaetomium olivaceum SD-80A, g7489, induces a substantial pleiotropic effect on the expression of SM BGCs. The C. olivaceum SD-80A ∆g7489 strain exhibited significant changes in morphology, sporulation ability, and secondary metabolic profile, resulting in the emergence of new compound peaks. Notably, three polyketides (A1–A3) and one asterriquinone (A4) were isolated from this mutant strain. Furthermore, our study explored the BGCs of A1–A4, confirming the function of two polyketide synthases (PKSs). Collectively, our findings highlight the promising potential of molecular epigenetic approaches for the elucidation of novel active compounds and their biosynthetic elements in Chaetomium species. This finding holds great significance for the exploration and utilization of Chaetomium resources.Key points• Deletion of a class I histone deacetylase activated secondary metabolite gene clusters.• Three polyketides and one asterriquinone were isolated from HDAC deleted strain.• Two different PKSs were reported in C. olivaceum SD-80A.

Histone acetylation in the development and regeneration of craniofacial hard tissue

Craniofacial hard tissue mainly includes craniofacial bone and tooth, which is one of the important parts of the mouth-jaw system. Congenital aplasia, tumors and trauma can cause large craniofacial hard tissue defects, which are detrimental to the facial appearance and function of patients, and affect the physical and mental health of patients. Histone acetylation modification is the earliest and most widely studied histone modification, which is an epigenetic modification mechanism jointly regulated by histone acetyltransferase and histone deacetylase. In this paper, we will review the research progress of histone acetylation mediated by histone acetyltransferase and histone deacetylase in the development and regeneration of craniofacial hard tissue.

Paeoniflorin exerts anti-PTSD effects in adult rats by modulating hippocampus and amygdala histone acetylation modifications in response to early life stress

Early life stress (ELS) can cause long-term changes by epigenetic factors, especially histone acetylation modification, playing a crucial role, affect normal cognition, mood, and behavior, and increase susceptibility to post-traumatic stress disorder (PTSD) in adulthood. It has been found that paeoniflorin (PF) can cross the blood-brain barrier to exert anti-PTSD effects on adult PTSD rats. However, whether PF can alleviate the harmful effects caused by ELS in adulthood has not yet been reported. Therefore, to explore the relationship between ELS and PTSD susceptibility in adulthood and its mechanism, in this study, SPS was used as a stressor of ELS, and the mathematical tool Z-normalization was employed as an evaluation criterion of behavioral resilience susceptibility. To investigate the regulatory mechanism of PF on histone acetylation in the hippocampus and amygdala of ELS rats in adulthood, using changes in HATs/HDACs as the entry point, meanwhile, the epigenetic marks (H3K9 and H4K12) in the key brain regions of ELS (hippocampus and amygdala) were evaluated, and the effects of PF on behavioral representation and PTSD susceptibility were observed. This study found that ELS lead to a series of PTSD-like behaviors in adulthood and caused imbalance of HATs/HDACs ratio in the hippocampus and amygdala, which confirms that ELS is an important risk factor for the development of PTSD in adulthood. In addition, paeoniflorin may improve ELS-induced PTSD-like behaviors and reduce the susceptibility of ELS rats to develop PTSD in adulthood by modulating the HATs/HDACs ratio in the hippocampus and amygdala.

The ING protein Fng2 associated with RPD3 HDAC complex for the regulation of fungal development and pathogenesis in wheat head blight fungus

ING proteins display a high level of evolutionary conservation across various species, and play a crucial role in modulating histone acetylation levels, thus regulating various important biological processes in yeast and humans. Filamentous fungi possess distinct biological characteristics that differentiate them from yeasts and humans, and the specific roles of ING proteins in filamentous fungi remain largely unexplored. In this study, an ING protein, Fng2, orthologous to the yeast Pho23, has been identified in the wheat head blight fungus Fusarium graminearum. The deletion of the FNG2 gene resulted in defects in vegetative growth, conidiation, sexual reproduction, plant infection, and deoxynivalenol (DON) biosynthesis. Acting as a global regulator, Fng2 exerts negative control over histone H4 acetylation and governs the expression of over 4000 genes. Moreover, almost half of the differentially expressed genes in the fng3 mutant were found to be co-regulated by Fng2, emphasizing the functional association between these two ING proteins. Notably, the fng2 fng3 double mutant exhibits significantly increased H4 acetylation and severe defects in both fungal development and pathogenesis. Furthermore, Fng2 localizes within the nucleus and associates with the FgRpd3 histone deacetylase (HDAC) to modulate gene expression. Overall, Fng2's interaction with FgRpd3, along with its functional association with Fng3, underscores its crucial involvement in governing gene expression, thereby significantly influencing fungal growth, asexual and sexual development, pathogenicity, and secondary metabolism.

Decreased Ubiquitination and Acetylation of Histones 3 and 4 Are Associated with Obesity-Induced Disorders of Spermatogenesis in Mice.

Obesity, a chronic metabolic disorder, is related to cardiovascular diseases, diabetes, cancer, and reproductive disorders. The relationship between obesity and male infertility is now well recognized, but the mechanisms involved are unclear. We aimed to observe the effect of obesity on spermatogenesis and to investigate the role of histone ubiquitination and acetylation modifications in obesity-induced spermatogenesis disorders. Thirty male C57BL/6J mice were randomly divided into two groups. The control group was fed with a general maintenance diet (12% fat), while a high-fat diet (HFD) group was fed with 40% fat for 10 weeks; then, they were mated with normal females. The fertility of male mice was calculated, testicular and sperm morphology were observed, and the expression levels of key genes and the levels of histone acetylation and ubiquitination modification during spermatogenesis were detected. The number of sperm was decreased, as well as the sperm motility, while the number of sperm with malformations was increased. In the testes, the mRNA and protein expression levels of gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), chromosome region maintenance-1 protein (CRM1), high-mobility group B2 (HMGB2), phosphoglycerate kinase 2 (PGK2), and testicular angiotensin-converting enzyme (tACE) were decreased. Furthermore, obesity led to a decrease in ubiquitinated H2A (ubH2A) and reduced levels of histone H3 acetylation K18 (H3AcK18) and histone H4 acetylation K5, K8, K12, and K16 (H4tetraAck), which disrupted protamine 1 (Prm1) deposition in testis tissue. These results suggest that low levels of histone ubiquitination and acetylation are linked with obesity-induced disorders during spermatogenesis, contributing to a better understanding of obesity-induced damage to male reproduction.

Artemisinin Confers Cytoprotection toward Hydrogen Peroxide-Induced Cell Apoptosis in Retinal Pigment Epithelial Cells in Correlation with the Increased Acetylation of Histone H4 at Lysine 8.

Increased oxidative stress is one of the critical pathologies inducing age-related macular degeneration (AMD), characterized by retinal pigment epithelial (RPE) cell damage and death. The unbalanced acetylation and deacetylation of histones have been implicated in AMD pathogenesis or hydrogen peroxide (H2O2)-induced cell damage. Therefore, strategies aimed at controlling the balance between acetylation and deacetylation may effectively protect RPE cells from oxidative damage. Artemisinin is an antimalarial lactone drug derived from Artemisia annua, with antioxidant activity known to modulate histone acetylation in the brain, but its effect on the retina is unknown. In this study, we aimed to investigate whether Artemisinin exerts a cytoprotective effect on oxidative stress-induced apoptosis in RPE cells by regulating histone acetylation. We hypothesized that Artemisinin confers cytoprotection toward H2O2-induced apoptosis in RPE cells through this mechanism. In the present study, we found that Artemisinin at a sub-clinic dosage of 20 μM inhibited the H2O2-induced cell viability decrease and B-cell lymphoma 2 (Bcl-2) protein level decrease and attenuated the H2O2-induced decrease in the histone H4 lysine (Lys) 8 acetylation [Acetyl-H4 (Lys 8)] level in the retinal RPE cell line D407. As expected, histone deacetylase inhibitor Trichostatin A at the concentration of 250 nM increased the Acetyl-H4 (Lys 8) level in D407 cells and attenuated the H2O2-induced cell viability decrease and apoptosis. Similar findings were obtained using adult RPE (ARPE)19 cells, another human RPE cell line, and primary human RPE cell cultures. In conclusion, these results confirmed our hypothesis and indicated that Artemisinin attenuated H2O2-induced apoptosis in apparent correlation with the increase in the Acetyl-H4 (Lys 8) level, which is associated with gene transcription and cell survival. By modulating histone acetylation, Artemisinin may restore the balance between acetylation and deacetylation and enhance the resistance and survival of RPE cells under oxidative stress. Our study provides novel mechanistic insights into the effect of Artemisinin on histone acetylation and apoptosis in RPE cells and supports the potential application of Artemisinin in the prevention and/or treatment of AMD.

Electroacupuncture regulates histone acetylation of Bcl-2 and Caspase-3 genes to improve ischemic stroke injury

BackgroundImbalances between Bcl-2 and caspase-3 are significant evidence of apoptosis, which is considered an influential factor in rapidly occurring neuronal cell death and the decline of neurological function after stroke. Studies have shown that acupuncture can reduce poststroke brain cell damage via either an increase in Bcl-2 or a reduction in caspase-3 exposure. The current study aimed to investigate whether acupuncture could modulate Bcl-2 and caspase-3 expression through histone acetylation modifications, which could potentially serve as a neuroprotective mechanism. MethodsThis study used TTC staining, Nissl staining, Clark neurological system score, and Evans Blue (EB) extravasation to evaluate neurological damage following stroke. The expression of Bcl-2/caspase-3 mRNA was detected by real-time fluorescence quantification of PCR (real-time PCR), whereas the protein expression levels of Bcl-2, Bax, caspase-3, and cleaved caspase-3 were assessed using western blotting. TUNEL staining of the ischemic cortical neurons determined apoptosis in the ischemic cortex. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities, along with the protein performance of AceH3, H3K9ace, and H3K27ace, were detected to evaluate the degree of histone acetylation. The acetylation enrichment levels of H3K9 and K3K27 in the Bcl-2/caspase-3 gene were assessed using Chromatin Immunoprecipitation (ChIP) assay. ResultsOur data demonstrated that electroacupuncture (EA) exerts a significant neuroprotective effect in middle cerebral artery occlusion (MCAO) rats, as evidenced by a reduction in infarct volume, neuronal damage, Blood-Brain Barrier (BBB) disruption, and decreased apoptosis of ischemic cortical neurons. EA treatment can promote the mRNA and protein expression of the Bcl-2 gene in the ischemic brain while reducing the mRNA and protein expression levels of caspase-3 and effectively decreasing the protein expression levels of Bax and cleaved caspase-3. More importantly, EA treatment enhanced the level of histone acetylation, including Ace-H3, H3K9ace, and H3K27ace, significantly enhanced the occupancy of H3K9ace/H3K27ace at the Bcl-2 promoter, and reduced the enrichment of H3K9ace and H3K27ace at the caspase-3 promoter. However, the Histone Acetyltransferase inhibitor (HATi) treatment reversed these effects. ConclusionsOur data demonstrated that EA mediated the expression levels of Bcl-2 and caspase-3 in MCAO rats by regulating the occupancy of acetylated H3K9/H3K27 at the promoters of these two genes, thus exerting a cerebral protective effect in ischemic reperfusion (I/R) injury.

Comprehensive analysis of histone acetylation-related genes in glioblastoma and lower-grade gliomas: Insights into drug sensitivity, molecular subtypes, immune infiltration, and prognosis.

The purpose of this research was to study the impact of histone acetylation on glioblastoma multiforme (GBM) and lower-grade gliomas (LGG) and its potential implications for patient prognosis. We aimed to assess the histone acetylation score (HAs) and its relationship with key genes involved in histone acetylation regulation. The TCGA-GBMLGG dataset, which provides comprehensive genomic and clinical information, was utilized for this study. We calculated the HAs by analyzing the expression levels of histone acetylation-related genes, including histone acetyltransferases and histone deacetylases, in GBM and LGG patients. Kaplan-Meier survival analysis was performed to evaluate the prognostic value of the HAs. Furthermore, correlation analysis and differential expression analysis were conducted to assess the relationship between the HAs and key genes involved in histone acetylation regulation, as well as the expression differences of immune checkpoint genes. Our analysis revealed a significant association between the HAs and patient prognosis, with higher HAs correlating to poorer outcomes in GBM and LGG patients. We observed a positive correlation between the HAs and key genes involved in histone acetylation regulation, indicating their potential role in modulating histone acetylation levels. Moreover, we found significant expression differences for immune checkpoint genes between high and low HAs groups, suggesting a potential impact of histone acetylation on the immune response in GBM and LGG. This study highlights the significance of histone acetylation in GBM and LGG. The HAs demonstrated prognostic value, indicating its potential as a clinically relevant biomarker. The correlation between the HAs and key genes involved in histone acetylation regulation provides insights into the underlying mechanisms driving histone acetylation dysregulation in GBM and LGG. Furthermore, the observed expression differences of immune checkpoint genes suggest a potential link between histone acetylation and the immune response. These findings contribute to our understanding of the molecular basis of GBM and LGG and have implications for personalized treatment approaches targeting histone acetylation and the immune microenvironment. Further validation and functional studies are needed to confirm these findings and explore potential therapeutic strategies.

Sphingolipid metabolism controls mammalian heart regeneration

Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.

Epigenetic modification of histone acetylation in the sensorimotor cortex after intracerebral hemorrhage.

Epigenetic regulation is involved in post-stroke neuroplasticity. We investigated the effects of intracerebral hemorrhage (ICH) on histone acetylation and gene expression related to neuronal plasticity in the bilateral sensorimotor cortices, which may affect post-stroke sensorimotor function. Wistar rats were randomly divided into the SHAM and ICH groups. We performed ICH surgery stereotaxically based on the microinjection of a collagenase solution in the ICH group. Foot fault and cylinder tests were performed to evaluate motor functions at 4-time points, including pre-ICH surgery. The amount of acetyl histones and the mRNA expression of neurotrophic factors crucial to neuroplasticity in the bilateral sensorimotor cortices were analyzed approximately 2 weeks after ICH surgery. Sensorimotor functions of the ICH group were inferior to those of the SHAM group during 2 weeks post-ICH. ICH increased the acetylation of histone H3 and H4 over the sham level in the ipsilateral and contralateral cortices. ICH increased the mRNA expression of IGF-1, but decreased the expression of BDNF compared with the sham level in the ipsilateral cortex. The present study suggests that histone acetylation levels are enhanced in bilateral sensorimotor cortices after ICH, presenting an altered epigenetic platform for gene expressions related to neuronal plasticity.