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Objective: To investigate the expressions of microRNA-155 (miR-155) and histone deacetylase 2 (HDAC2) in peripheral blood mononuclear cells (PBMC) of patients with sudden deafness (SSNHL) and their clinical significances. Methods: 112 patients with SSNHL who were treated in our hospital from February 2017 to September 2018 were selected as the study subjects, and they were referred to as sudden deafness group, and another 115 healthy examinees in the same period were compared and studied as normal group. The relative expression levels of miR-155, HDAC2, ICAM-1, TNF-α and interleukin-8 (IL-8) in PBMC of all subjects were detected by real-time fluorescence quantitative analysis (qRT-PCR). Pearson method was used to analyze the relationships between miR-155, HDAC2 and the expressions of ICAM-1, TNF-α, IL-8, and miR-155 and the expression of HDAC2 in PBMC of SSNHL patients. Logistic regression analysis was used to analyze the risk factors of SSNHL. The predictive diagnostic values of miR-155 and HDAC2 in PBMC for SSNHL were evaluated. Results: The relative expression levels of miR-155, ICAM-1, TNF-α and IL-8 in PBMC of sudden deafness group were significantly higher than those of normal group (P<0.05), while the relative expression levels of HDAC2 were significantly lower than those of normal group (P<0.05). In SSNHL patients, miR-155 were positively correlated with the expression levels of ICAM-1, TNF-α and IL-8 (P<0.05). The expression level of HDAC2 was negatively correlated with the expression levels of TNF-α and IL-8 (P<0.05). The expression level of miR-155 in PBMC of SSNHL patients was negatively correlated with HDAC2 (P<0.05). MiR-155, ICAM-1, TNF-α and IL-8 were risk factors for SSNHL (P<0.05), while HDAC2 was protective factor for SSNHL (P<0.05). The areas under curve (AUC) of miR-155 and HDAC2 in PBMC for SSNHL diagnosis were 0.855 and 0.835 respectively, the truncation values of which were 1.449 and 0.959 respectively, at this moment, the sensitivities were 75.0% and 81.3% respectively, and the corresponding specificities were 86.1% and 70.1% respectively. The AUC of combined diagnosis of SSNHL was 0.927, and the sensitivity and specificity were 86.7% and 85.3% respectively. Conclusions: The expressions of miR-155 is high and HDAC2 is low in PBMC of SSNHL patients, which are negatively correlated, and both of them may participate in the occurrence and development of SSNHL through mutual influence, which is a risk factor of SSNHL. The combination of the two can effectively improve the predictive diagnostic value of SSNHL. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Histone deacetylase (HDAC) 6 plays a role in oncogenic transformation and cancer metastasis via tubulin deacetylation, making it a critical target for anticancer drug design. However, lack of selectivity shown by many of the current HDAC6 inhibitors in clinical use and trials prompts the continuous search for selective inhibitors. Here, 10 pharmacophore hypotheses were developed based on the 3D common features of training set of 20 HDAC inhibitors in clinical use and trials. The hypotheses were validated using a test set of another 20 HDAC inhibitors along with 400 inactive (decoys) molecules based on Güner-Henry pharmacophore scoring method. Hypothesis 1 consisting of 1 H-bond donor, 1 H-bond acceptor and 2 hydrophobic features, was used to screen "DruglikeDiverse" database using Biovia Discovery Studio 4.5. The top 10 hit compounds were selected based on the pharmacophore fit values (>3.00). Their binding affinity against HDAC6 compared to class I HDACs (1, 2, 3 & 8) and a class IIa member (HDAC7), was calculated by molecular docking using AutoDock4. The stability of binding modes of 2 potential HDAC6-selective inhibitors (ENA501965 and IBS399024) was examined by 30 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software. Both ligands showed potential stability in HDAC6 active site over time. Therefore, these may provide additional scaffolds for further optimization towards the design of safe, potent and selective HDAC6 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Enhancers are distal cis-regulatory elements that control gene expression. Despite an increasing appreciation of the importance of enhancers in cellular function and disease, our knowledge of enhancer-regulated transcription is very limited. Nascent RNA sequencing technologies, such as global nuclear run-on sequencing (GRO-seq) and precision run-on sequencing (PRO-seq), not only provide a direct and reliable measurement of enhancer activity, but also allow for quantifying transcription of enhancers and target genes simultaneously, making these technologies extremely useful for exploring enhancer-mediated regulation. Results: Nascent RNA sequencing analysis (NRSA) provides a comprehensive view of enhancer-mediated gene regulation. NRSA not only outperforms existing methods for enhancer identification, but also enables annotation and quantification of active enhancers, and prediction of their target genes. Furthermore, NRSA identifies functionally important enhancers by integrating 1) nascent transcriptional changes in enhancers and their target genes and 2) binding profiles from regulator(s) of interest. Applied to wildtype and histone deacetylase 3 (Hdac3) knockout mouse livers, NRSA showed that HDAC3 regulates RNA polymerase recruitment through both proximal (promoter) and distal (enhancer) regulatory elements. Integrating ChIP-seq with PRO-seq data, NRSA prioritized enhancers based on their potential contribution to mediating HDAC3 regulation. Conclusions: NRSA will greatly facilitate the usage of nascent RNA sequencing techniques and accelerate the study of enhancer-mediated regulation. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) is responsible for severe morbidity and mortality in animals and humans worldwide. miRNAs are a class of small noncoding single-stranded RNA molecules that can negatively regulate gene expression and play important roles in virus-host interaction. However, the roles of miRNAs in IAV infection are still not fully understood. Here, we profiled the cellular miRNAs of A549 cells infected with A/goose/Jilin/hb/2003 (H5N1) and a comparison A/Beijing/501/2009 (H1N1). miRNA microarray and quantitative PCR analysis showed that several miRNAs were differentially expressed in A549 cells during IAV infection. Subsequently, we demonstrated that IAV replication was essential for the regulation of these miRNAs, and bioinformatic analysis revealed that the targets of these miRNAs affected biological processes relevant to IAV replication. Specifically, miR-21-3p was found to be down-regulated in IAV-infected A549 cells and selected for further detailed analysis. Target prediction and functional study illustrated that miR-21-3p repressed the expression of HDAC8 by targeting its 3′UTR. Furthermore, we confirmed miR-21-3p could promote virus replication, which was similar to the result of knocking down HDAC8, indicating that miR-21-3p promoted IAV replication by suppressing HDAC8 expression. Altogether, our results suggest a potential host defense against IAV through down-regulation of miR-21-3p. [ABSTRACT FROM AUTHOR]

Pathogens have developed sophisticated strategies to evade the immune response, among which manipulation of host cellular epigenetic mechanisms plays a prominent role. In the last decade, modulation of histone acetylation in host cells has emerged as an efficient strategy of bacterial immune evasion. Virulence factors and metabolic products of pathogenic microorganisms alter expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to suppress transcription of host defense genes through epigenetic changes in histone acetylation marks. This new avenue of pathogen-host interactions is particularly important in light of introduction of HDAC inhibitors into clinical practice. Considerable effort is currently being applied to better understand the effects of HDAC inhibitors on the quality of immune responses to pathogens and to characterize the therapeutic potential of these compounds in microbial infections. In this review, we will discuss the recently discovered mechanisms utilized by bacteria to facilitate their survival within infected hosts through subversion of the host acetylation system and the effects of acetylation modulators, including HDAC inhibitors and bromodomain-containing BET protein inhibitors, on innate immune responses against microbial pathogens. Integration of these two lines of experimental evidence provides critical information on the perspectives of epigenetic therapies targeting protein acetylation in infectious diseases. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effects of 1,25(OH) 2 D 3 on the apoptosis of human hepatocellular carcinoma (HCC) cells. The effects of 1,25(OH) 2 D 3 on the proliferation and apoptosis of human HCC cells by regulating histone deacetylase 2 (HDAC2) were assessed by MTT assay and flow cytometry. The effects of 1,25(OH) 2 D 3 on the expressions of related proteins in the apoptosis pathway by regulating HDAC2 as well as the mechanism were studied by Western blot and quantitative real-time PCR. A nude mouse model of HCC xenograft was established. A control group, a 1,25(OH) 2 D 3 treatment group, a 1,25(OH) 2 D 3 + HDAC2 overexpression group, an HDAC2 interference group and an HDAC2 overexpression group were set. The tumor volume was recorded, and histopathological changes were observed by HE staining. 1,25(OH) 2 D 3 inhibited the proliferation of HepG2 cells and induced their apoptosis. Overexpression of HDAC2 attenuated the inhibitory effects of 1,25(OH) 2 D 3 on the proliferation of HepG2 cells and its ability to induce apoptosis. In the 1,25(OH) 2 D 3 + HDAC2 overexpression group, the expressions of p53, Bax, DR5 and caspase 8 were significantly lower but the expression of Bcl-2 was significantly higher than those of the 1,25(OH) 2 D 3 treatment group (P < 0.05). Compared with the control group, 1,25(OH) 2 D 3 treatment and HDAC2 interference groups had significantly decreased tumor volumes and promoted apoptosis of HCC cells in tumor tissues. Overexpression of HDAC2 weakened the inhibitory effects of 1,25(OH) 2 D 3 on tumor volume and its ability to induce apoptosis in tissues. A large area of tumor cells underwent necrosis in 1,25(OH) 2 D 3 treatment and HDAC2 interference groups. In the 1,25(OH) 2 D 3 + HDAC2 overexpression group, both the area of necrosis and cell volume decreased. In conclusion, 1,25(OH) 2 D 3 inhibited the proliferation of HCC cells and induced their apoptosis by down-regulating the expression of HDAC2, up-regulating p53, and regulating its downstream mitochondria-mediated pathway and the exogenous DR-mediated pathway. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms have been proposed to contribute to persistent aspects of addiction-related behaviors. One family of epigenetic molecules that may regulate maladaptive behavioral changes produced by cocaine use are the histone deacetylases (HDACs)-key regulators of chromatin and gene expression. In particular, the class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) respond to changes in neuronal activity by modulating their distribution between the nucleus and cytoplasm-a process controlled in large part by changes in phosphorylation of conserved residues. Cocaine triggers a transient nuclear accumulation of HDAC5 that functions to limit the development of cocaine reward behavior. However, the role and regulation of the close family member, HDAC4, in cocaine behaviors remain largely unknown. In this study, we report that cocaine and cAMP signaling in striatum produced differential phosphorylation and subcellular localization of HDAC4 and HDAC5. Unlike HDAC5, cocaine exposure induced a modest hyperphosphorylation and nuclear export of HDAC4. Genetic deletion of HDAC4 in the nucleus accumbens reduced acute cocaine-produced locomotion, maximum locomotor sensitization and cocaine reward-related behavior. Interestingly, overexpression of an HDAC4 cytoplasm-concentrated mutant (S266E) increased cocaine reward behavior in the cocaine conditioned place preference assay, suggesting that cocaine-induced nuclear export of HDAC4 might function to facilitate the development of cocaine reward behaviors through a role in the cell cytoplasm. Together, our findings suggest that, despite high sequence homology, HDAC4 and HDAC5 are oppositely regulated by cocaine-induced signaling in vivo and have distinct roles in regulating cocaine behaviors. [ABSTRACT FROM AUTHOR]

Background. To date, 4 classes of histone deacetylases (HDACs) have been identified in humans. Class I HDACs are zinc-dependent and NAD+-independent enzymes, and include 4 isoforms closely related to yeast RPD3: HDAC1, 2, 3, and 8. Objectives. The aims of the study were to quantitatively evaluate the expression of HDAC3 in colorectal cancer (CRC) and to correlate its expression levels with clinicopathological parameters. Material and methods. We characterized expression patterns of HDAC3 as class I HDAC isoforms in a cohort of 48 CRC patients by quantitative (real-time) reverse transcription polymerase chain reaction (RT-PCR). In addition, the potential relationship between HDAC3 expression levels and clinicopathological parameters in patients suffering from CRC was explored. Results. We found that HDAC3 was highly expressed in colorectal tumors compared to normal colorectal tissues (p < 0.05). Furthermore, we found significant correlations between HDAC3 expression levels and tumor differentiation grades (p < 0.05). Conclusions. In this prospective study we identified a pronounced HDAC3 expression pattern in CRC. Our findings support an important role of HDAC3 as a complementary molecular marker for existing histopathological diagnostic elements; it might also have applications in prognostic and targeted therapy. Furthermore, HDAC3 can be used as a biomarker to differentiate between tumor borders and margins, and it may also be useful for characterizing field cancerization in CRC. [ABSTRACT FROM AUTHOR]

The class IIa histone deacetylases (HDACs) play important roles in the central nervous system during diverse biological processes such as synaptic plasticity, axon regeneration, cell apoptosis, and neural differentiation. Although it is known that HDAC5 regulates neuronal differentiation, neither the physiological function nor the regulation of HDAC5 in neuronal differentiation is clear. Here, we identify HDAC5 as an inhibitor of neurite elongation and show that HDAC5 is regulated by the brain enriched microRNA miR-124 and miR-9. We discover that HDAC5 inhibits neurite extension both in differentiated P19 cells and primary neurons. We also show that the neuronal membrane glycoprotein GPM6A (M6a) is a direct target gene of HDAC5 regulated transcriptional factor MEF2C. HDAC5 inhibits neurite elongation, acting at least partially via a MEF2C/M6a signaling pathway. We also confirmed the miR-124/miR-9 regulated HDAC5-MEF2C-M6a pathway regulates neurite development in primary neurons. Thus, HDAC5 emerges as a cellular conductor of MEF2C and M6a activity and is regulated by miR-124 and miR-9 to control neurite development. [ABSTRACT FROM AUTHOR]

The downstream targets of histone deacetylase 1 (HDAC1) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and it is also unknown whether activation of peroxisome proliferator-activated receptor γ (PPARγ) modulates HDAC1 and its down-stream targets in PASMCs. The present study aims to address these issues. Our results showed that PDGF dose- and time-dependently induced PASMC proliferation, and this was accompanied by an increase of HDAC1 and cyclin-dependent kinase 4 (CDK4) protein expression as well as a reduction of microRNA-124 (miR-124). Pre-silencing of HDAC1 with small interfering RNA (siRNA) abolished PDGF-induced miR-124 down-regulation, CDK4 protein up-regulation, and PASMC proliferation. In addition, over-expression of miR-124 reversed CDK4 protein elevation and PASMC proliferation caused by PDGF. We further found that pre-incubation of PASMCs with pioglitazone, an agonist of PPARγ receptors, significantly increased PPARγ expression and activity, and blocked PDGF-stimulated cell proliferation by regulating HDAC1-mediated miR-124 and CDK4 expression. Our study indicates that HDAC1/miR-124/CDK4 axis plays an important role in PDGF-induced PASMC proliferation, and activation of PPARγ inhibits PASMC proliferation by acting on HDAC1 pathway. [ABSTRACT FROM AUTHOR]

Although ERα activation properties have been intensively studied, this is not the case for their repressive properties. In this report, the ERα ligand binding domain (LBD) is shown to interact both with a deacetylase function and with HDAC1 and HDAC3. Ligands do not affect binding to the deacetylase activity or to HDAC1. In distinction, E2 reduced LBD binding to HDAC3, whereas Tmx had no effect. Knock-down of either HDAC1 or 3 led to increased transcriptional activity by both HDACs, presumably by decreased repression. In distinction, only HDAC3 knock-down led to increased activity in the presence of Tmx. In summary, ERα differentially interacts with HDACs 1 and 3 to regulate transcriptional activity. [ABSTRACT FROM AUTHOR]

Adultonset autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either the PKD1 or PKD2 gene, leading to malfunction of their gene products, polycystin 1 or 2. Histone deacetylase 6 (HDAC6) expression and activity are increased in PKD1 mutant renal epithelial cells. Here we studied the effect of ACY-1215, a specific HDAC6 inhibitor, on cyst growth in ADPKD. Treatment with ACY-1215 slowed cyst growth in a mouse model of ADPKD that forms massive cysts within 3 wk after knockout of polycystin 1 function. It also prevented cyst formation in MDCK.2 cells, an in vitro model of cystogenesis, and in an ADPKD cell line derived from the proximal tubules from a pkd1-/-.mouse (PN cells). In PN cells ACY-1215 also reduced the size of already established cysts. We found that ACY-1215 lowered cAMP levels and protein expression of adenylyl cyclase 6. Our results suggest that HDAC6 could potentially serve as a therapeutic target in ADPKD. [ABSTRACT FROM AUTHOR]

Background: Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase that promotes many cellular processes that lead to cell transformation and tumour development. We previously documented an interaction between Ran-Binding Protein M (RanBPM) and HDAC6 and found that RanBPM expression inhibits HDAC6 activity. RanBPM is part of a putative E3 ubiquitin ligase complex, termed the C-terminal to LisH (CTLH) complex. Here, we investigated the involvement of the CTLH complex on HDAC6 inhibition and assessed the outcome of this regulation on the cellular motility induced by HDAC6.Methods: Cell lines (Hela, HEK293 and immortalized mouse embryonic fibroblasts) stably or transiently downregulated for several components of the CTLH complex were employed for the assays used in this study. Interactions of HDAC6, RanBPM and muskelin were assessed by co-immunoprecipitations. Quantifications of western blot analyses were employed to evaluate acetylated α-tubulin levels. Confocal microscopy analyses were used to determine microtubule association of HDAC6 and CTLH complex members. Cell migration was evaluated using wound healing assays.Results: We demonstrate that RanBPM-mediated inhibition of HDAC6 is dependent on its association with HDAC6. We show that, while HDAC6 does not require RanBPM to associate with microtubules, RanBPM association with microtubules requires HDAC6. Additionally, we show that Twa1 (Two-hybrid-associated protein 1 with RanBPM) and MAEA (Macrophage Erythroblast Attacher), two CTLH complex members, also associate with α-tubulin and that muskelin, another component of the CTLH complex, is able to associate with HDAC6. Downregulation of CTLH complex members muskelin and Rmnd5A (Required for meiotic nuclear division homolog A) resulted in decreased acetylation of HDAC6 substrate α-tubulin. Finally, we demonstrate that the increased cell migration resulting from downregulation of RanBPM is due to the relief in inhibition of HDAC6 α-tubulin deacetylase activity.Conclusions: Our work shows that RanBPM, together with the CTLH complex, associates with HDAC6 and restricts cell migration through inhibition of HDAC6 activity. This study uncovers a novel function for the CTLH complex and suggests that it could have a tumour suppressive role in restricting HDAC6 oncogenic properties. [ABSTRACT FROM AUTHOR]

The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2 −/− mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sphingosine kinase 1 (SK1), which functions as a proinflammatory enzyme. SK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation. Therefore, there is a need to develop highly potent SK2 inhibitors with selectivity over SK1 to clearly define the role of SK2 in autoimmune/inflammatory disease. Structural determinants of SK2 relative to SK1 will enable the design of selective SK2 inhibitors. [ABSTRACT FROM AUTHOR]

The pro-inflammatory cytokine interferon- γ ( IFN- γ) is critical for activating innate and adaptive immunity against tumours and intracellular pathogens. Interferon- γ is secreted at the fetal-maternal interface in pregnant women and mice. The outer layer of the placenta in contact with maternal blood is composed of semi-allogeneic trophoblast cells, which constitute the fetal component of the fetal-maternal interface. The simultaneous presence of pro-inflammatory IFN- γ and trophoblast cells at the fetal-maternal interface appears to represent an immunological paradox, for trophoblastic responses to IFN- γ could potentially lead to activation of maternal immunity and subsequent attack of the placenta. However, our previous studies demonstrate that IFN- γ responsive gene ( IRG) expression is negatively regulated in human and mouse trophoblast cells. In human cytotrophoblast and trophoblast-derived choriocarcinoma cells, janus kinase signalling is blocked by protein tyrosine phosphatases ( PTPs), whereas in mouse trophoblast, histone deacetylases ( HDACs) inhibit IRG expression. Here, we used genome-wide transcriptional profiling to investigate the collective roles of PTPs and HDACs on regulation of IRG expression in human choriocarcinoma cells. Logic-rules were optimized to derive regulatory modes governing gene expression patterns observed upon different combinations of treatment with PTP and HDAC inhibitors. The results demonstrate that IRGs can be divided into several categories in human choriocarcinoma cells, each of which is subject to distinct mechanisms of repression. Hence, the regulatory modes identified in this study suggest that human trophoblast and choriocarcinoma cells may evade the potentially deleterious consequences of exposure to IFN- γ by using several overlapping mechanisms to block IRG expression. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective Immunosuppression therapy following lung transplantation fails to prevent chronic rejection in many patients, which is associated with lack of suppression of cytotoxic mediators and pro-inflammatory cytokines in peripheral blood T and natural killer T ( NKT)-like cells. Histone acetyltransferases ( HATs) and histone deacetylases ( HDACs) upregulate/downregulate pro-inflammatory gene expression, respectively; however, differences in the activity of these enzymes following lung transplant are unknown. We hypothesized decreased HDAC2 expression and increased HAT expression in pro-inflammatory lymphocytes following lung transplant. Methods Blood was collected from 18 stable lung transplant patients and 10 healthy age-matched controls. Intracellular pro-inflammatory cytokines and HAT/ HDAC2 expression were determined in lymphocyte subsets following culture using flow cytometry. Results A loss of HDAC2 in cluster of differentiation ( CD) 8+ T and NKT-like cells in transplant patients compared with controls was noted ( CD8+ T: 28 ± 10 (45 ± 10), CD8+ NKT-like: 30 ± 13 (54 ± 16) (mean ± SD transplant) (control)). Loss of HDAC2 was associated with an increased percentage of CD8+ T and NKT-like cells expressing perforin, granzyme b, interferon gamma ( IFN-γ) and TNF-α (no change in HAT expression in any lymphocyte subset). There was a negative correlation between loss of HDAC2 expression by CD8+ T cells with cumulative dose of prednisolone and time post-transplant. Treatment with 10 mg/L theophylline + 1 µmol/L prednisolone or 2.5 ng/ mL cyclosporine A synergistically upregulated HDAC2 and inhibited IFN-γ and TNF-α production by CD8+ T and NKT-like lymphocytes. Conclusion HDAC2 is decreased in CD8+ T and NKT-like pro-inflammatory lymphocytes following lung transplant. Treatment options that increase HDAC2 may improve graft survival. [ABSTRACT FROM AUTHOR]

The transcription factors NF-κB and p53 as well as their crosstalk determine the fate of tumor cells upon therapeutic interventions. Replicative stress and cytokines promote signaling cascades that lead to the co-regulation of p53 and NF-κB. Consequently, nuclear p53/NF-κB signaling complexes activate NF-κB-dependent survival genes. The 18 histone deacetylases (HDACs) are epigenetic modulators that fall into four classes (I-IV). Inhibitors of histone deacetylases (HDACi) become increasingly appreciated as anti-cancer agents. Based on their effects on p53 and NF-κB, we addressed whether clinically relevant HDACi affect the NF-κB/p53 crosstalk. The chemotherapeutics hydroxyurea, etoposide, and fludarabine halt cell cycle progression, induce DNA damage, and lead to DNA fragmentation. These agents co-induce p53 and NF-κB-dependent gene expression in cell lines from breast and colon cancer and in primary chronic lymphatic leukemia (CLL) cells. Using specific HDACi, we find that the class I subgroup of HDACs, but not the class IIb deacetylase HDAC6, are required for the hydroxyurea-induced crosstalk between p53 and NF-κB. HDACi decrease the basal and stress-induced expression of p53 and block NF-κB-regulated gene expression. We further show that class I HDACi induce senescence in pancreatic cancer cells with mutant p53. [ABSTRACT FROM AUTHOR]

Chondroitin sulfate (CS) proteoglycans are abundant extracellular and cell surface molecules that consist of a protein core to which highly sulfated CS chains are covalently attached. The CS backbone is composed of repeating disaccharide units [-GlcA-GalNAc-] n , and during synthesis the CS chains acquire structural variability due to the action of sulfotransferases. Specific sulfation patterns are recognized by a large variety of proteins, including growth factors, morphogens, and extracellular matrix proteins, and these interactions regulate key events in development and normal physiology. Therefore, it is important to understand how gene expression of CS sulfotransferases is regulated. We previously found that Wnt signaling regulates the sulfation patterns of cell-associated CS chains by suppressing expression of chondroitin 4-O-sulfotaransferase-1 ( C4ST-1 ), a CS biosynthetic enzyme. Here we investigated the mechanism underlying the regulation of C4ST-1 gene expression by Wnt/β-catenin signaling. Although C4ST-1 mRNA of 3′-UTR contains three binding sites for microRNAs (miRNA), these miRNAs played little role in controlling C4ST-1 gene expression. In contrast, the suppression of C4ST-1 gene expression by Wnt/β-catenin signaling can be recovered by treatment with trichostatin A, but not with 5′-aza-2′-deoxycytidine. These results suggest that the Wnt/β-catenin signal pathway controls C4ST-1 gene expression mainly through histone deacetylase. [ABSTRACT FROM AUTHOR]

Light is a major environmental factor regulating flowering time, thus ensuring reproductive success of higher plants. In contrast to our detailed understanding of light quality and photoperiod mechanisms involved, the molecular basis underlying high light-promoted flowering remains elusive. Here we show that, in Arabidopsis, a chloroplast- derived signal is critical for high light-regulated flowering mediated by the FLOWERING LOCUS C (FLC). We also demonstrate that PTM, a PHD transcription factor involved in chloroplast retrograde signaling, perceives such a signal and mediates transcriptional repression of FLC through recruitment of FVE, a component of the histone deacetylase complex. Thus, our data suggest that chloroplasts function as essential sensors of high light to regulate flowering and adaptive responses by triggering nuclear transcriptional changes at the chromatin level. [ABSTRACT FROM AUTHOR]

The functional withdrawal of progesterone is mediated by the enhanced expression ratio of the 2 progesterone receptor (PR) isoforms, PRA and PRB, and causes the pregnant human myometrium to switch from a quiet state to a state of excitation–contraction and subsequent laboring. However, the precise mechanisms responsible for alterations in PRA and PRB expression during human parturition have yet to be resolved. In the present study, we report that PRA expression was increased in myometrium samples during labor (P < .001), concomitant with reduced expression of histone deacetylase 1 (HDAC1; P < .01). These results were further confirmed in the laboratory using cultured primary myometrial cells to investigate the effects of HDAC1 knockdown or overexpression. Finally, we verified that HDAC1 downregulated PRA expression by binding to the promoter region of PRA as confirmed by chromatin immunoprecipitation assays (P < .01) and real-time polymerase chain reaction (P < .001). Therefore, the present study not only demonstrates the epigenetic mechanisms underlying human labor but also provides a potential clinical strategy with which to intervene and prevent labor disorders. [ABSTRACT FROM AUTHOR]

In fission yeast, the ste11 gene encodes the master regulator initiating the switch from vegetative growth to gametogenesis. In a previous paper, we showed that the methylation of H3K4 and consequent promoter nucleosome deacetylation repress ste11 induction and cell differentiation (Materne et al., 2015) but the regulatory steps remain poorly understood. Here we report a genetic screen that highlighted H2B deubiquitylation and the RSC remodeling complex as activators of ste11 expression. Mechanistic analyses revealed more complex, opposite roles of H2Bubi at the promoter where it represses expression, and over the transcribed region where it sustains it. By promoting H3K4 methylation at the promoter, H2Bubi initiates the deacetylation process, which decreases chromatin remodeling by RSC. Upon induction, this process is reversed and efficient NDR (nucleosome depleted region) formation leads to high expression. Therefore, H2Bubi represses gametogenesis by opposing the recruitment of RSC at the promoter of the master regulator ste11 gene. [ABSTRACT FROM AUTHOR]

Recent thymic emigrants are newly generated T cells that need to undergo postthymic maturation to gain functional competency and enter the long-lived naive T cell pool. The mechanism of T cell maturation remains incompletely understood. Previously, we demonstrated that the transcriptional repressor NKAP is required for T cell maturation. Because NKAP associates with histone deacetylase 3 (HDAC3), we examined whether HDAC3 is also required for T cell maturation. Although thymic populations are similar in CD4-cre HDAC3 conditional knockout mice compared with wild-type mice, the peripheral numbers of CD4+ and CD8+ T cells are dramatically decreased. In the periphery, the majority of HDAC3-deficient naive T cells are recent thymic emigrants, indicating a block in T cell maturation. CD55 upregulation during T cell maturation is substantially decreased in HDAC3-deficient T cells. Consistent with a block in functional maturation, HDAC3-deficient peripheral T cells have a defect in TNF licensing after TCR/CD28 stimulation. CD4-cre HDAC3 conditional knockout mice do not have a defect in intrathymic migration, thymic egress, T cell survival, or homeostasis. In the periphery, similar to immature NKAP-deficient peripheral T cells, HDAC3-deficient peripheral T cells were bound by IgM and complement proteins, leading to the elimination of these cells. In addition, HDAC3-deficient T cells display decreases in the sialic acid modifications on the cell surface that recruit natural IgM to initiate the classical complement pathway. Therefore, HDAC3 is required for T cell maturation. [ABSTRACT FROM AUTHOR]

Summary Inhibitors of histone deacetylases (HDACi) hold considerable therapeutic promise as clinical anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compounds are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compound, UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression, resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biological activities in suppressing tumor cell proliferation support further preclinical development of the UF010 class of compounds for potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Salt-inducible kinase 2 (SIK2) is an AMP-activated protein kinase (AMPK) related kinase abundantly expressed in adipose tissue. Our aim was to identify molecular targets and functions of SIK2 in adipocytes, and to address the role of PKA-mediated phosphorylation of SIK2 on Ser358. Modulation of SIK2 in adipocytes resulted in altered phosphorylation of CREB-regulated transcription co-activator 2 (CRTC2), CRTC3 and class IIa histone deacetylase 4 (HDAC4). Furthermore, CRTC2, CRTC3, HDAC4 and protein phosphatase 2A (PP2A) interacted with SIK2, and the binding of CRTCs and PP2A to wild-type but not Ser358Ala SIK2, was reduced by cAMP elevation. Silencing of SIK2 resulted in reduced GLUT4 (also known as SLC2A4) protein levels, whereas cells treated with CRTC2 or HDAC4 siRNA displayed increased levels of GLUT4. Overexpression or pharmacological inhibition of SIK2 resulted in increased and decreased glucose uptake, respectively. We also describe a SIK2-CRTC2-HDAC4 pathway and its regulation in human adipocytes, strengthening the physiological relevance of our findings. Collectively, we demonstrate that SIK2 acts directly on CRTC2, CRTC3 and HDAC4, and that the cAMP-PKA pathway reduces the interaction ofSIK2 with CRTCs and PP2A. Downstream, SIK2 increases GLUT4 levels and glucose uptake in adipocytes. [ABSTRACT FROM AUTHOR]

Background A link between histone deacetylases ( HDACs) and intestinal inflammation has been established. HDAC inhibitors that target gut-selective inflammatory pathways represent a potential new therapeutic strategy in patients with refractory inflammatory bowel diseases ( IBD). Aims To review the use of selective HDAC inhibitors to treat gut inflammation and to highlight potential improvements in selectivity/sensitivity by additional targeting of HDAC-regulating micro RNAs (mi RNAs). Methods Original articles and reviews have been identified using PubMed search terms: 'histone deacetylase', ' HDAC inhibitor', 'inflammatory bowel disease', 'gut inflammation,' and 'micro RNA and HDAC'. Results The use of butyrate in distal colitis provided the first evidence that inhibition of HDACs decreases intestinal inflammation in IBD. HDAC inhibitors, such as valproic acid, vorinostat and givinostat, reduce inflammation and tissue damage in experimental murine colitis. Potential mechanisms of action for HDAC inhibitors include increased apoptosis, reduction of pro-inflammatory cytokine release, regulation of transcription factors and modulation of HDAC-regulatory mi RNAs. HDAC2, HDAC3, HDAC6, HDAC9 and HDAC10 isoforms seem to be specifically involved in chronic intestinal inflammation, justifying the use of selective inhibitors as new therapeutic strategies in IBD. Controlling mi RNAs for these isoforms can be identified. Conclusions The pro-inflammatory influence of HDACs in the gut has been confirmed, but mostly in murine studies. Considerably more human data are required to permit development of selective HDAC inhibitors for IBD treatment. Inhibition of key HDAC isoforms in combination with modulation of HDAC-regulatory mi RNAs has potential as a novel therapeutic approach. [ABSTRACT FROM AUTHOR]

Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased neutrophil gelatinase-associated lipocalin expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin, and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Furthermore, renal EGFR signaling is subject to regulation by this class of HDACs. [ABSTRACT FROM AUTHOR]

Highlights: [•] HDAC6 interacts with HDAC11 in antigen presenting cells. [•] HDAC6 is a positive regulator of IL10 production. [•] Nuclear role of HDAC6 as transcriptional regulator. [•] HDACs as modulators of the APC plasticity to trigger T-cell activation. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase (MMP) 9 plays an important role in the degradation of the extracellular matrix in fetal membranes, and pathological activation of MMP-9 can lead to preterm birth. In nongestational tissues, modulation of histone deacetylases (HDACs) regulates MMP-9 expression. The aim of this study was to determine whether class I to III HDACs regulate MMP-9 expression and activity in primary amnion cells. Class I and II HDAC regulation of MMP-9 was assessed using the general class I and II HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), the class I HDACi MS-275, and the class II HDACi MC1568. Class III HDAC regulation of MMP-9 was assessed using the SIRT1 activators resveratrol and SRT1720 as well as SIRT1 small interfering RNA (siRNA). Primary amnion epithelial cells were incubated with 1 ng/mL interleukin (IL) 1β in the absence or presence of 0.3 μmol/L TSA, 5 μmol/L SAHA, 2.5 μmol/L MS-275, 2.5 μmol/L MC1568, 50 μmol/L resveratrol, or 10 μmol/L SRT1720 for 20 hours. We found that the class I and II HDACi TSA and SAHA and the class II HDACi MC1568 significantly decreased IL-β-induced MMP-9 gene and pro-MMP-9 expression in primary amnion cells. There was, however, no effect of the class I HDACi MS-275 on IL-β-induced MMP-9 expression. On the other hand, inhibition of class III HDAC SIRT1 using siRNA significantly augmented IL-1β-induced MMP-9, and SIRT1 activation using resveratrol and SRT1720 inhibited IL-1β-induced MMP-9 expression. In summary, class I to III HDACs differentially regulate inflammation-induced MMP-9 expression in primary amnion cells. [ABSTRACT FROM AUTHOR]

Objective We examined the expression of IL-33 as an indicator of an innate immune response in relapsing remitting MS (RRMS) and controls. We proposed a link between the expression of IL-33 and IL-33 regulated genes to histone deacetylase (HDAC) activity and in particular HDAC3, an enzyme that plays a role in the epigenetic regulation of a number genes including those which regulate inflammation. Methods Using TaqMan low density arrays, flow cytometry and ELIZA, expression of IL-33, and family of innate immune response genes which regulate cytokine gene expression was examined in RRMS patients and controls. Results Intracellular expression of IL-33 and IL-33 regulated genes are increased in patients with RRMS. In addition, following in vitro culture with TLR agonist lipopolysaccharide (LPS), there is increased induction of both IL-33 and HDAC3 in RRMS patients over that seen in controls. Also, culture of PBMC with IL-33 led to the expression of genes which overlapped with that seen in RRMS patients suggesting that the gene expression signature seen in RRMS is likely to be driven by IL-33 mediated innate immune pathways. Expression of levels of IL-33 but not IL-1 (another gene regulated by TLR agonists) is completely inhibited by Trichostatin A (TSA) establishing a closer regulation of IL-33 but not IL-1 with HDAC. Interpretation These results demonstrate the over expression of innate immune genes in RRMS and offer a causal link between the epigenetic regulation by HDAC and the induction of IL-33. [ABSTRACT FROM AUTHOR]

Molecular mechanisms that maintain lineage integrity of helper T cells are largely unknown. Here we show histone deacetylases 1 and 2 (HDAC1 and HDAC2) as crucial regulators of this process. Loss of HDAC1 and HDAC2 during late T cell development led to the appearance of major histocompatibility complex (MHC) class II-selected CD4+ helper T cells that expressed CD8-lineage genes such as Cd8a and Cd8b1. HDAC1 and HDAC2-deficient T helper type 0 (TH0) and TH1 cells further upregulated CD8-lineage genes and acquired a CD8+ effector T cell program in a manner dependent on Runx-CBFβ complexes, whereas TH2 cells repressed features of the CD8+ lineage independently of HDAC1 and HDAC2. These results demonstrate that HDAC1 and HDAC2 maintain integrity of the CD4 lineage by repressing Runx-CBFβ complexes that otherwise induce a CD8+ effector T cell-like program in CD4+ T cells. [ABSTRACT FROM AUTHOR]

Type I interferon is induced shortly following viral infection and represents a first line of host defense against a majority of viral pathogens. Not surprisingly, both replication and latency of gammaherpesviruses, ubiquitous cancer-associated pathogens, are attenuated by type I interferon, although the mechanism of attenuation remains poorly characterized. Gammaherpesviruses also target histone deacetylases (HDACs), a family of pleiotropic enzymes that modify gene expression and several cell signaling pathways. Specifically, we have previously shown that a conserved gammaherpesvirus protein kinase interacts with HDAC1 and -2 to promote gammaherpesvirus replication in primary macrophages. In the current study, we have used genetic approaches to show that expression of HDAC1 and -2 is critical for induction of a type I interferon response following gammaherpesvirus infection of primary macrophages. Specifically, expression of HDAC1 and -2 was required for phosphorylation of interferon regulatory factor 3 (IRF3) and accumulation of IRF3 at the beta interferon promoter in gammaherpesvirus-infected primary macrophages. To our knowledge, this is the first demonstration of a specific role for HDAC1 and -2 in the induction of type I interferon responses in primary immune cells following virus infection. Furthermore, because HDAC1 and -2 are overexpressed in several types of cancer, our findings illuminate potential side effects of HDAC1- and -2-specific inhibitors that are currently under development as cancer therapy agents. [ABSTRACT FROM AUTHOR]

Abstract: Fibrosis, which is defined as excessive accumulation of fibrous connective tissue, contributes to the pathogenesis of numerous diseases involving diverse organ systems. Cardiac fibrosis predisposes individuals to myocardial ischemia, arrhythmias and sudden death, and is commonly associated with diastolic dysfunction. Histone deacetylase (HDAC) inhibitors block cardiac fibrosis in pre-clinical models of heart failure. However, which HDAC isoforms govern cardiac fibrosis, and the mechanisms by which they do so, remains unclear. Here, we show that selective inhibition of class I HDACs potently suppresses angiotensin II (Ang II)-mediated cardiac fibrosis by targeting two key effector cell populations, cardiac fibroblasts and bone marrow-derived fibrocytes. Class I HDAC inhibition blocks cardiac fibroblast cell cycle progression through derepression of the genes encoding the cyclin-dependent kinase (CDK) inhibitors, p15 and p57. In contrast, class I HDAC inhibitors block agonist-dependent differentiation of fibrocytes through a mechanism involving repression of ERK1/2 signaling. These findings define novel roles for class I HDACs in the control of pathological cardiac fibrosis. Furthermore, since fibrocytes have been implicated in the pathogenesis of a variety of human diseases, including heart, lung and kidney failure, our results suggest broad utility for isoform-selective HDAC inhibitors as anti-fibrotic agents that function, in part, by targeting these circulating mesenchymal cells. [Copyright &y& Elsevier]

Highlights: [•] Doxorubicin induces the down-expression of HDAC1 to exacerbate DNA damage. [•] Doxorubicin specifically downregulate the expression of HDAC1 but not other HDACs. [•] HDAC1 is a target of miR-520h which was upregulated after doxorubicin treatment. [•] The effect of doxorubicin was impaired by exogenous HDAC1 or miR-520h inhibitors. [•] HDAC1 reduced γH2AX by interfering the interaction of doxorubicin with genomic DNA. [Copyright &y& Elsevier]

Background: Lithium and valproic acid (VPA) exhibit a robust neuroprotective and anti-tumor effects in neural cells and tumor cells. Results: Lithium significantly down-regulates HDAC1 at the translational level by targeting HDAC1 mRNA. Conclusion: The decrease in HDAC1 is essential for the lithium-mediated, autophagic degradation of mutant huntingtin. Significance: This report is the first demonstration that HDAC1 decreases in response to lithium treatment. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is the leading genetic cause of early childhood death worldwide and no therapy is available today. Many drugs, especially histone deacetylase inhibitors (HDACi), increase SMN levels. As all HDACi tested so far only mildly ameliorate the SMA phenotype or are unsuitable for use in humans, there is still need to identify more potent drugs. Here, we assessed the therapeutic power of the pan-HDACi JNJ-26481585 for SMA, which is currently used in various clinical cancer trials. When administered for 64 h at 100 nM, JNJ-26481585 upregulated SMN levels in SMA fibroblast cell lines, including those from non-responders to valproic acid. Oral treatment of Taiwanese SMA mice and control littermates starting at P0 showed no overt extension of lifespan, despite mild improvements in motor abilities and weight progression. Many treated and untreated animals showed a very rapid decline or unexpected sudden death. We performed exploratory autopsy and histological assessment at different disease stages and found consistent abnormalities in the intestine, heart and lung and skeletal muscle vasculature of SMA animals, which were not prevented by JNJ-26481585 treatment. Interestingly, some of these features may be only indirectly caused by α-motoneuron function loss but may be major life-limiting factors in the course of disease. A better understanding of - primary or secondary - non-neuromuscular organ involvement in SMA patients may improve standard of care and may lead to reassessment of how to investigate SMA patients clinically. [ABSTRACT FROM AUTHOR]

Histone acetylation and deacetylation can be dynamically regulated in response to environmental stimuli and play important roles in learning and memory. Pharmacological inhibition of histone deacetylases (HDACs) improves performance in learning tasks; however, many of these classical agents are "pan-HDAC" inhibitors, and their use makes it difficult to determine the roles of specific HDACs in cognitive function. We took a genetic approach using mice lacking the class I HDACs, HDAC1 or HDAC2, in postmitotic forebrain neurons to investigate the specificity or functional redundancy of these HDACs in learning and synaptic plasticity. We show that selective knock-out of Hdac2 led to a robust acceleration of the extinction rate of conditioned fear responses and a conditioned taste aversion as well as enhanced performance in an attentional set-shifting task. Hdac2 knock-out had no impact on episodic memory or motor learning, suggesting that the effects are task-dependent, with the predominant impact of HDAC2 inhibition being an enhancement in an animal's ability to rapidly adapt its behavioral strategy as a result of changes in associative contingencies. Our results demonstrate that the loss of HDAC2 improves associative learning, with no effect in nonassociative learning tasks, suggesting a specific role for HDAC2 in particular types of learning. HDAC2 may be an intriguing target for cognitive and psychiatric disorders that are characterized by an inability to inhibit behavioral responsiveness to maladaptive or no longer relevant associations. [ABSTRACT FROM AUTHOR]

HDACs epigenetically regulate cellular processes by modifying chromatin and influencing gene expression. We previously reported that conditional deletion of Hdac3 in osteo-chondroprogenitor cells with Osx1-Cre caused severe osteopenia due to abnormal maturation of osteoblasts. The mice were also smaller. To address the abnormal longitudinal growth in these animals, the role of Hdac3 in chondrocyte differentiation was evaluated. We found that Hdac3 is highly expressed in resting and prehypertrophic growth plate chondrocytes, as well as in articular chondrocytes. Hdac3-deficient chondrocytes entered hypertrophy sooner and were smaller than normal chondrocytes. Extracellular matrix production was suppressed as glycosaminoglycan secretion and production of aggrecan, osteopontin, and matrix extracellular phosphoglycoprotein were reduced in Hdac3-deficient chondrocytes. These phenotypes led to the hypothesis that the Akt/mTOR pathway was repressed in these Hdac3-deficient chondrocytes because Akt promotes hypertrophy and matrix production in many tissues. The phosphorylation and activation of Akt, its substrate mTOR, and the mTOR substrate, p70 S6 kinase, were indeed reduced in Hdac3-deficient primary chondrocytes as well as in chondrocytes exposed to HDAC inhibitors. Expression of constitutively active Akt restored phosphorylation of mTOR and p70 S6K and matrix gene expression levels. Reduced phosphorylation of Akt and its substrates in Hdac3-deficient or HDAC inhibitors treated chondrocytes correlated with increased expression of the phosphatase Phlpp1. Hdac3 associated with a Phlpp1 promoter region containing Smad binding elements and was released after TGFβwas added to the culture. These data demonstrate that Hdac3 controls chondrocyte hypertrophy and matrix content by repressing Phlpp1 expression and facilitating Akt activity. [ABSTRACT FROM AUTHOR]

Summary: The Wilms'' tumor 1 protein WT1 is a transcriptional regulator that is involved in cell growth and differentiation. The transcriptional corepressor BASP1 interacts with WT1 and converts WT1 from a transcriptional activator to a repressor. Here, we demonstrate that the N-terminal myristoylation of BASP1 is required in order to elicit transcriptional repression at WT1 target genes. We show that myristoylated BASP1 binds to nuclear PIP2, which leads to the recruitment of PIP2 to the promoter regions of WT1-dependent target genes. BASP1''s myristoylation and association with PIP2 are required for the interaction of BASP1 with HDAC1, which mediates the recruitment of HDAC1 to the promoter and elicits transcriptional repression. Our findings uncover a role for myristoylation in transcription, as well as a critical function for PIP2 in gene-specific transcriptional repression through the recruitment of histone deacetylase. [Copyright &y& Elsevier]

Abstract: Increasing evidence suggest that epigenetic mechanisms (e.g. histone modification by histone deacetylases) play a major role in the pathogenesis of Hodgkin''s lymphoma (HL). We treated HL cell lines with the histone deacetylase inhibitor vorinostat and investigated the gene expression profile of these cells by using DNA microarrays. Vorinostat inhibited cell proliferation and induced chances in the gene expression profile of HL cells, including down regulation of interleukin-26 and CD30. Vorinostat also increased sensitivity for cisplatin. Our data suggest that the combination of vorinostat and chemotherapy might be an interesting option for patients with chemoresistant HL. [Copyright &y& Elsevier]

Histone acetylation has been implicated with the pathogenesis of neuropsychiatric disorders and targeting histone deacetylases (HDACs) using HDAC inhibitors was shown to be neuroprotective and to initiate neuroregenerative processes. However, little is known about the role of individual HDAC proteins during the pathogenesis of brain diseases. HDAC1 was found to be upregulated in patients suffering from neuropsychiatric diseases. Here, we show that virus-mediated overexpression of neuronal HDAC1 in the adult mouse hippocampus specifically affects the extinction of contextual fear memories, while other cognitive abilities were unaffected. In subsequent experiments we show that under physiological conditions, hippocampal HDAC1 is required for extinction learning via a mechanism that involves H3K9 deacetylation and subsequent trimethylation of target genes. In conclusion, our data show that hippocampal HDAC1 has a specific role in memory function. [ABSTRACT FROM AUTHOR]

The recent discovery of functional brown adipocytes in adult humans illuminates the potential of these cells in the treatment of obesity and its associated diseases. In rodents, brown adipocyte-like cells are known to be recruited in white adipose tissue (WAT) by cold exposure or β-adrenergic stimulation, but the molecular machinery underlying this phenomenon is not fully understood. Here, we show that inducible brown adipogenesis is mediated by the microRNA miR-196a. We found that miR-196a suppresses the expression of the white-fat gene Hoxc8 post-transcriptionally during the brown adipogenesis of white fat progenitor cells. In mice, miR-196a is induced in the WAT-progenitor cells after cold exposure or β-adrenergic stimulation. The fat-specific forced expression of miR-196a in mice induces the recruitment of brown adipocyte-like cells in WAT. The miR-196a transgenic mice exhibit enhanced energy expenditure and resistance to obesity, indicating the induced brown adipocyte-like cells are metabolically functional. Mechanistically, Hoxc8 targets and represses C/EBPβ, a master switch of brown-fat gene program, in cooperation with histone deacetylase 3 (HDAC3) through the C/EBPβ 3′ regulatory sequence. Thus, miR-196a induces functional brown adipocytes in WAT through the suppression of Hoxc8, which functions as a gatekeeper of the inducible brown adipogenesis. The miR-196a-Hoxc8-C/EBPβ signaling pathway may be a therapeutic target for inducing brown adipogenesis to combat obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Microglial polarization with M1/M2 phenotype shifts and the subsequent neuroinflammatory responses are vital contributing factors for spinal cord injury (SCI)-induced secondary injury. Nuclear factor-κB (NF-κB) is considered the central transcription factor of inflammatory mediators, which plays a crucial role in microglial activation. Lysine acetylation of STAT1 seems necessary for NF-kB pathway activity, as it is regulated by histone deacetylases (HDACs). There have been no studies that have explained if HDAC inhibition by valproic acid (VPA) affects the NF-κB pathway via acetylation of STAT1 dependent of HDAC activity in the microglia-mediated central inflammation following SCI. We investigated the potential molecular mechanisms that focus on the phenotypic transition of microglia and the STAT1-mediated NF-κB acetylation after a VPA treatment.Methods: The Basso-Beattie-Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, and Nissl staining were employed to determine the neuroprotective effects of VPA treatment after SCI. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (INF)-γ was used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of VPA treatment. Immunofluorescent staining and Western blot analysis were used to detect HDAC3 nuclear translocation, activity, and NF-κB signaling pathway activation to evaluate the effects of VPA treatment. The impact of STAT1 acetylation on NF-kB pathway and the interaction between STAT1 and NF-kB were assessed to evaluate anti-inflammation effects of VPA treatment and also whether these effects were dependent on a STAT1/NF-κB pathway to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after SCI.Results: The results showed that the VPA treatment promoted the phenotypic shift of microglia from M1 to M2 phenotype and inhibited microglial activation, thus reducing the SCI-induced inflammatory factors. The VPA treatment upregulation of the acetylation of STAT1/NF-κB pathway was likely caused by the HDAC3 translocation to the nucleus and activity. These results indicated that the treatment with the VPA suppressed the expression and the activity of HDAC3 and enhanced STAT1, as well as NF-κB p65 acetylation following a SCI. The acetylation status of NF-kB p65 and the complex with NF-κB p65 and STAT1 inhibited the NF-kB p65 transcriptional activity and attenuated the microglia-mediated central inflammatory response following SCI.Conclusions: These results suggested that the VPA treatment attenuated the inflammatory response by modulating microglia polarization through STAT1-mediated acetylation of the NF-κB pathway, dependent of HDAC3 activity. These effects led to neuroprotective effects following SCI. [ABSTRACT FROM AUTHOR]

The article presents a study which highlights the role of intestinal epithelial cells (IECs) in sensing environmental and microbial signals and in the regulation of cellular and molecular networks in tissue homeostasis. It refers to the expression of epigenome-modifying enzyme histone deacetylase 3 (HDAC3) in IECs to be used against commensal bacterial. Details on HDAC3 is given such as its importance for transcriptional regulation, metabolism, and suppression of inflammation in mice.

The article discusses the role of Histone deacetylases (HDACs) in macrophages in context to the gene expression program. It mentions the targeting of HDAC to the nonhistone proteins, and highlights the need of recognition of the transcriptional co-regulators and identification of the sequence-specific transcription factors.