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In the vertebrate brain, GABAergic cell development and neurotransmission are important for the establishment of neural circuits. Various intrinsic and extrinsic factors have been identified to affect GABAergic neurogenesis. However, little is known about the epigenetic control of GABAergic differentiation in the developing brain. Here, we report that the number of GABAergic neurons dynamically changes during the early tectal development in the Xenopus brain. The percentage of GABAergic neurons is relatively unchanged during the early stages from stage 40 to 46 but significantly decreased from stage 46 to 48 tadpoles. Interestingly, the histone acetylation of H3K9 is developmentally decreased from stage 42 to 48 (about 3.5 days). Chronic application of valproate acid (VPA), a broad-spectrum histone deacetylase (HDAC) inhibitor, at stage 46 for 48 h increases the acetylation of H3K9 and the number of GABAergic cells in the optic tectum. VPA treatment also reduces apoptotic cells. Electrophysiological recordings show that a VPA induces an increase in the frequency of mIPSCs and no changes in the amplitude. Behavioral studies reveal that VPA decreases swimming activity and visually guided avoidance behavior. These findings extend our understanding of histone modification in the GABAergic differentiation and neurotransmission during early brain development.

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Hepatocellular Carcinoma (HCC) is the most frequent malignant tumor of the liver, but its prognosis is poor. Histone acetylation is an important epigenetic regulatory mode that modulates chromatin structure and transcriptional status to control gene expression in eukaryotic cells. Generally, histone acetylation and deacetylation processes are controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Dysregulation of histone modification is reported to drive aberrant transcriptional programmes that facilitate liver cancer onset and progression. Emerging studies have demonstrated that several HDAC inhibitors exert tumor-suppressive properties via activation of various cell death molecular pathways in HCC. However, the complexity involved in the epigenetic transcription modifications and non-epigenetic cellular signaling processes limit their potential clinical applications. This review brings an in-depth view of the oncogenic mechanisms reported to be related to aberrant HCC-associated histone acetylation, which might provide new insights into the effective therapeutic strategies to prevent and treat HCC.

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Substance use induces long-lasting behavioral changes and drug craving. Increasing evidence suggests that epigenetic gene regulation contributes to the development and expression of these long-lasting behavioral alterations. Here we systematically review extensive evidence from rodent models of drug-induced changes in epigenetic regulation and epigenetic regulator proteins. We focus on histone acetylation and histone methylation in a brain region important for drug-related behaviors: the nucleus accumbens. We also discuss how experimentally altering these epigenetic regulators via systemically administered compounds or nucleus accumbens-specific manipulations demonstrate the importance of these proteins in the behavioral effects of drugs and suggest potential therapeutic value to treat people with substance use disorder. Finally, we discuss limitations and future directions for the field of epigenetic studies in the behavioral effects of addictive drugs and suggest how to use these insights to develop efficacious treatments.

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An extensive body of literature suggested a possible role of the microtubule-associated protein Tau in chromatin functions and/or organization in neuronal, non-neuronal, and cancer cells. How Tau functions in these processes remains elusive. Here we report that Tau expression in breast cancer cell lines causes resistance to the anti-cancer effects of histone deacetylase inhibitors, by preventing histone deacetylase inhibitor-inducible gene expression and remodeling of chromatin structure. We identify Tau as a protein recognizing and binding to core histone when H3 and H4 are devoid of any post-translational modifications or acetylated H4 that increases the Tau's affinity. Consistent with chromatin structure alterations in neurons found in frontotemporal lobar degeneration, Tau mutations did not prevent histone deacetylase-inhibitor-induced higher chromatin structure remodeling by suppressing Tau binding to histones. In addition, we demonstrate that the interaction between Tau and histones prevents further histone H3 post-translational modifications induced by histone deacetylase-inhibitor treatment by maintaining a more compact chromatin structure. Altogether, these results highlight a new cellular role for Tau as a chromatin reader, which opens new therapeutic avenues to exploit Tau biology in neuronal and cancer cells.

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Background: Histone acetylation modification has been found to be correlated the development of renal carcinoma; however, its role in clear cell renal carcinoma (ccRCC) remains to be investigated. Thus, this study aimed to identify the molecular subtypes and establish a relevant score based on histone acetylation modification in ccRCC. Methods: Gene expression and mutation data were retrieved from The Cancer Genome Atlas database. Molecular subtypes were identified by unsupervised clustering based on histone acetylation regulators expression, and the molecular and clinical characteristics including survival, tumor microenvironment, gene set variation, immune cell infiltration, and immune checkpoints in each subtype were investigated. Next, we employed univariate Cox analysis to analyze these genes and established acetylation-related score by lasso regression analysis. Furthermore, we investigated the differences including survival, signaling pathways, mutational landscape, and tumor mutation burden (TMB) between high-risk and low-risk groups. The established score was validated by receiver operating curve and univariate and multivariate Cox regression analyses. We also established a nomogram including acetylation score, age, gender, grade, and stage and verified it by decision curve analysis and calibration plot. The E-MTAB-1980 cohort from the ArrayExpress database was employed as a reference to validate the established score. Results: Thirty-three types of histone acetylation regulators were employed in this study, and two clusters were identified. The two clusters presented significant differences in survival, tumor microenvironment, immune cell infiltration, immune checkpoints, and signaling pathways. Furthermore, an acetylation-related score, composed of six genes (BRD9, HDAC10, KAT2A, KAT5, BRDT, SIRT1, KAT6A, HDAC5), was verified to be significantly associated with prognosis and TMB. Thus, the established scores were successfully verified by the validated cohort, and the nomogram was constructed and successfully validated. Conclusion: The identification of the histone acetylation-related subtypes and score in our study may help reveal the potential relation between histone acetylation and immunity and provide novel insights for the development of individualized therapy for ccRCC.

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BACKGROUND: Immune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML. METHODS: To analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1. RESULTS: We observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells. CONCLUSIONS: Our results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML.

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BACKGROUND: With the development of radiotherapy technology, radiotherapy has been increasingly used to treat primary hepatocellular carcinoma (HCC). However, due to radioresistance and the intolerance of the adjacent organs to radiation, the effects of radiotherapy are often unsatisfactory. Therefore, it is necessary to study radiosensitization in HCC. METHOD: A microarray was used to analyze the genes that were significantly associated with radiosensitivity. HCC cells, HepG2 and MHCC97H, were subjected to radiation in vitro. Real-time PCR was performed to determine MIR22HG (microRNA22 host gene) and miR-22-5p expression levels. Western blotting was performed to determine histone expression levels. A histone deacetylase (HDAC) whole cell assay was used to determine the activity of HDAC2. MTT, colony formation, 5-ethynyl-2'-deoxyuridine, and wound healing assays were performed to examine the function of MIR22HG and miR-22-5p in cellular radiosensitivity. Chromatin immunoprecipitation-PCR was used to confirm that HDAC2 affects the acetylation level of the MIR22HG promoter region. Finally, animal experiments were performed to demonstrate the in vivo effect of MIR22HG on the radiosensitivity of hepatoma. RESULTS: Irradiation can up-regulate MIR22HG expression and down-regulate HDAC2 expression. Inhibition of HDAC2 expression promotes histone acetylation in the MIR22HG promoter region and up-regulates MIR22HG expression. MIR22HG can increase radiosensitivity via miR-22-5p in HCC. CONCLUSION: Inhibition of HDAC2 expression promotes histone acetylation in the MIR22HG promoter region, thereby up-regulating the expression of MIR22HG and promoting the production of miR-22-5p, and ultimately increasing the sensitivity of liver cancer radiotherapy.

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SCOPE: Deoxynivalenol (DON) and its acetylated derivatives 3-acetyl-DON (3-Ac-DON) and 15-acetyl-DON (15-Ac-DON) are important mycotoxins of concern in the modern food chain. METHODS AND RESULTS: The present study reveals that the rate of de-acetylation in in vitro anaerobic fecal incubations decreased in the order rat > mouse > human > pig for 3-Ac-DON, and mouse > human > rat > pig for 15-Ac-DON. The ratio between the de-acetylation rate of 3-Ac-DON and 15-Ac-DON varies with the species. Scaling of the kinetic parameters to the in vivo situation results in catalytic efficiencies decreasing in the order human > rat > pig > mouse for 3-Ac-DON and human > pig > rat > mouse for 15-Ac-DON. The results obtained indicate that in mice, 3-Ac-DON can be fully deconjugated while 15-Ac-DON cannot. In rats, pigs, and humans, both 3-Ac-DON and 15-Ac-DON can be totally transformed by gut fecal microbiota during the estimated intestinal residence time. A correlation analysis between the deacetylation rate and the relative abundance of the microbiome suggests Lachnospiraceae may be involved in the deacetylation process. CONCLUSION: It is concluded that interspecies differences in deacetylation of acetylated DONs exist but that in risk assessment assumption of complete intestinal deconjugation provides an adequate approach.

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Cellulose nanofibers, which are troublesome to spin into fibers, can be easily fabricated by post-regeneration of its acetate-derived threads. Cellulose is a natural polymer; it enjoys better biocompatibility, cellular mimicking, and hydrophilic properties than its proportionate analog. Herein, we regenerated acetate-free nanofibers by alkaline de-acetylation of as-spun nanofibers. The resultant cellulose nanofibers previously loaded with hydroxyapatite (HAp) were immobilized using silver (Ag) nanoparticles (NPs) by reduction of adsorbed Ag ions on using sodium borohydride. These amalgamated nanofibers were characterized for SEM, EDX, TEM, FTIR, and hydrophilicity tests revealing the existence of both HAp and Ag NPs in/on the nanofiber scaffolds. The de-acetylation of composite nanofibers resulted in spontaneous hydrophilicity. These nanofibers were cytocompatible, as resolved by MTT assay conducted on chicken embryo fibroblasts. The SEM of the samples after cell culture revealed that these composites allowed a proliferation of the fibroblasts over and within the nanofiber network, and increased concentration of HAp levitated the excessive of apatite formation as well as increased cell growth. The antimicrobial activity of these nanofibers was assessed on E. coli (BL21) and S. aureus, suggesting the potential of de-acetylated nanofibers to restrain bacterial growth. The degradation study for 10, 30, and 60 days indicated degradation of the fibers much is faster in enzymes as compared to degradation in PBS. The results certify that these nanofibers possess enormous potential for soft and hard tissue engineering besides their antimicrobial properties.

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Drugs targeting epigenetic mechanisms such as histone deacetylase inhibitors (HDACi) suppress tumor growth. HDACi also induce the expression of ligands for the cytotoxicity receptor NKG2D rendering tumors more susceptible to natural killer (NK) cell-dependent killing. The major acetylases responsible for the expression of NKG2D ligands (NKG2D-L) are CBP and p300. The role of the oncogene and transcriptional repressor SKI, an essential part of an HDAC-recruiting co-repressor complex, which competes with CBP/p300 for binding to SMAD3 in TGFß signaling, is unknown. Here we show that the siRNA-mediated downregulation of SKI in the pancreatic cancer cell lines Panc-1 and Patu8988t leads to an increased target cell killing by primary NK cells. However, the higher cytotoxicity of NK cells did not correlate with the induction of NKG2D-L. Of note, the expression of NKG2D-L and consequently NK cell-dependent killing could be induced upon LBH589 (LBH, panobinostat) or valproic acid (VPA) treatment irrespective of the SKI expression level but was significantly higher in pancreatic cancer cells upon genetic ablation of SKI. These data suggest that SKI represses the inducible expression of NKG2D-L. The combination of HDACi with NK cell-based immunotherapy is an attractive treatment option for pancreatic tumors, specifically for patients with high SKI protein levels.

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Mycotoxins are important food contaminants that commonly co-occur with modified mycotoxins such as mycotoxin-glucosides in contaminated cereal grains. These masked mycotoxins are less toxic, but their breakdown and release of unconjugated mycotoxins has been shown by mixed gut microbiota of humans and animals. The role of different bacteria in hydrolysing mycotoxin-glucosides is unknown, and this study therefore investigated fourteen strains of human gut bacteria for their ability to break down masked mycotoxins. Individual bacterial strains were incubated anaerobically with masked mycotoxins (deoxynivalenol-3-ß-glucoside, DON-Glc; nivalenol-3-ß-glucoside, NIV-Glc; HT-2-ß-glucoside, HT-2-Glc; diacetoxyscirpenol-α-glucoside, DAS-Glc), or unconjugated mycotoxins (DON, NIV, HT-2, T-2, and DAS) for up to 48 h. Bacterial growth, hydrolysis of mycotoxin-glucosides and further metabolism of mycotoxins were assessed. We found no impact of any mycotoxin on bacterial growth. We have demonstrated that Butyrivibrio fibrisolvens, Roseburia intestinalis and Eubacterium rectale hydrolyse DON-Glc, HT-2 Glc, and NIV-Glc efficiently and have confirmed this activity in Bifidobacterium adolescentis and Lactiplantibacillus plantarum (DON-Glc only). Prevotella copri and B. fibrisolvens efficiently de-acetylated T-2 and DAS, but none of the bacteria were capable of de-epoxydation or hydrolysis of α-glucosides. In summary we have identified key bacteria involved in hydrolysing mycotoxin-glucosides and de-acetylating type A trichothecenes in the human gut.

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This study characterizes chitin extracted from bio-sources of snail and periwinkle using varied combinations of acid and alkali concentrations. A three level factorial design of experiment with alkali and acid concentrations was used. FTIR, XRD and SEM were used to investigate the structural changes after treatments. Results reveal that both alkali and acid concentrations significantly affect the development of the functional groups and their intensities in the extracted chitin. A certain combination of concentration of acid and alkali can be used to obtain chitin with high degree of order (Crystallinity Index (CrI)>0.9) and a degree of de-acetylation (DD>50%). This results in combined high crystallinity and degree of de-acetylation. The study also established that certain combination of acid and alkali concentrations could lead to alpha to beta transformation in chitin structure.

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Mitochondria are highly dynamic organelles that change size and morphology by fusing together or dividing through fission. In response to cellular cues, signaling cascades may post-translationally modify mitochondria-shaping proteins, which lead to a change in mitochondria morphology. Here we show that nicotinamide (NAM), an inhibitor of sirtuin deacetylases, promotes degradation of mitochondria fusion protein mitofusin 1 (MFN1), suggesting that acetylation status of MFN1 is important for its protein stability. TIP60 but not PCAF acetyltransferase caused a reduction of MFN1 level. Meanwhile, siRNA-mediated knockdown of SIRT1 deacetylase caused a significant reduction of MFN1 whereas over-expression of SIRT1 increased its level in 293T cells. In vitro acetylation experiments showed that TIP60 increased the acetylation of MFN1 that was abolished by co-existence of SIRT1. Notably, MFN1 and SIRT1 levels were accumulated, along with mitochondria elongation under hypoxic conditions. Thus, the data suggest that mitochondria elongation under hypoxic condition is regulated through SIRT1-mediated MFN1 deacetylation and accumulation. The data provide an insight in the maintenance of cellular homeostasis through mitochondria morphological change.

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Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase that regulates longevity and enhances mitochondrial metabolism. Both activation and inhibition of SIRT1 were previously shown to ameliorate neuropathological mechanisms in Huntington's disease (HD), a neurodegenerative disease that selectively affects the striatum and cortex and is commonly linked to mitochondrial dysfunction. Thus, in this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models, namely striatal and cortical neurons isolated from YAC128 transgenic mice embryos, HD human lymphoblasts, and an in vivo HD model. HD cell models displayed a deregulation in mitochondrial membrane potential and respiration, implicating a decline in mitochondrial function. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.

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Inhibitors of histone deacetylases are frequently used against ischemia-induced injury, but the specific mechanisms of their action are poorly understood. Here, we report that following a 5-7-h oxygen-glucose deprivation (OGD) acetylation of histone H4 at residue K16 (H4K16Ac) decreases by 40-80% in both PC12 cells and primary neurons. This effect can be reverted by treatment with trichostatin A, or by supplementation with acetyl-CoA. A decrease in H4K16Ac levels can affect the expression of mitochondrial uncoupling protein 2 (UCP2), huntingtin-interacting protein 1 (HIP1) and Notch-pathway genes in a cell-specific manner. Thus, H4K16 acetylation is important for responses to ischemia and cell energy stress, and depends on both cytosolic and mitochondrial acetyl-CoA.

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