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Histone acetylation is an important, reversible post-translational protein modification and a hallmark of epigenetic regulation. However, little is known about the dynamics of this process, due to the lack of analytical methods that can capture site-specific acetylation and deacetylation reactions. We present a new approach that combines metabolic and chemical labeling (CoMetChem) using uniformly 13C-labeled glucose and stable isotope-labeled acetic anhydride. Thereby, chemically equivalent, fully acetylated histone species are generated, enabling accurate relative quantification of site-specific lysine acetylation dynamics in tryptic peptides using high-resolution mass spectrometry. We show that CoMetChem enables site-specific quantification of the incorporation or loss of lysine acetylation over time, allowing the determination of reaction rates for acetylation and deacetylation. Thus, the CoMetChem methodology provides a comprehensive description of site-specific acetylation dynamics.

Epigenetic changes, histone acetylation and deacetylation in chromatin have been intensively studied due to their significance in regulating the gene expression. According to the type of tumor, the levels of histone deacetylases (HDAC) are varied. HDAC inhibitors are a new promising class of compounds that inhibit the proliferation of tumor cells. In this study, the inhibitory efficacy of some HDAC inhibitors such as vorinostat, panobinostat, abexinostat, belinostat, resminostat, dacinostat and pracinostat was studied using molecular dynamics simulation. The inhibitory efficacy was estimated by computing the enzyme���s stability, positional stability of the individual amino acids and interaction energies of HDLP-inhibitor complexes. It is hoped that this investigation may improve our understanding of the atomic-level description of the inhibitor binding site and how the HDAC inhibitors change the environment of the enzyme���s active site. The results obtained from the root-mean-square deviation, the radius of gyration, solvent-accessible surface area, root-mean-square fluctuation, stride server and Ramachandran plot have revealed that the stability of HDLP enzyme with vorinostat, panobinostat and abexinostat is higher than the other studied complexes. According to the calculated values for MM-PBSA, LIE, semi-LIE binding free energies and interaction energies, the stability of the HDLP enzyme varies as panobinostat > abexinostat > vorinostat where resminostat complex showed relatively low stability. The ligandability and drugability values also give the same trend as above. The findings revealed that the panobinostat and abexinostat are potential lead compounds as reference inhibitor vorinostat. Therefore, it is possible to use these drugs as HDAC inhibitors in clinical practices. Also, the outcomes of this study could be utilized to identify new inhibitors for clinical research. Communicated by Ramaswamy H. Sarma

Epigenetic mechanisms such as histone acetylation and deacetylation participate in regulation of the genes involved in encystation of Entamoeba invadens. However, the histones and target residues involved, and whether the acetylation and deacetylation of the histones leads to the regulation of gene expression associated with the encystation of this parasite, remain unknown. In this study, we found that E. invadens histone H4 is acetylated in both stages of the parasite and is more highly acetylated during the trophozoite stage than in the cyst. Histone hyperacetylation induced by Trichostatin A negatively affects the encystation of E. invadens, and this inhibition is associated with the downregulation of the expression of genes implicated in the synthesis of chitin, polyamines, gamma-aminobutyric acid pathways and cyst wall proteins, all of which are important in the formation of cysts. Finally, in silico analysis and activity assays suggest that a class I histone deacetylase (EiHDAC3) could be involved in control of the expression of a subset of genes that are important in several pathways during encystation. Therefore, the identification of enzymes that acetylate and/or deacetylate histones that control encystation in E. invadens could be a promising therapeutic target for preventing transmission of other amoebic parasites such as E. histolytica, the causative agent of amoebiasis in humans.

Interplay between histone acetylation and deacetylation is one of the key components in epigenetic regulation of transcription. Here we report the requirement of Mo- HDA1-mediated histone deacetylation during asexual development and pathogenesis for the rice blast fungus, Magnaporthe oryzae. Structural similarity and phylogenetic analysis suggested that MoHDA1 is an ortholog of Saccharomyces cerevisiae Hda1, which is a representative member of class II histone deacetylases. Targeted deletion of MoHDA1 caused a little decrease in radial growth and large reduction in asexual sporulation. Comparison of acetylation levels for H3K9 and H3K14 showed that lack of MoHDA1 gene led to significant in- crease in H3K9 and H3K14 acetylation level, compared to the wild-type and complementation strain, confirm- ing that it is a bona fide histone deacetylase. Expression analysis on some of the key genes involved in asexual reproduction under sporulation-promoting condition showed almost no differences among strains, except for MoCON6 gene, which was up-regulated more than 6-fold in the mutant than wild-type. Although the deletion mutant displayed little defects in germination and subsequent appressorium formation, the mutant was compromised in its ability to cause disease. Wound- inoculation showed that the mutant is impaired in invasive growth as well. We found that the mutant was defective in appressorium-mediated penetration of host, but did not lose the ability to grow on the media containing H2O2. Taken together, our data suggest that MoHDA1-dependent histone deacetylation is important for efficient asexual development and infection of host plants in M. oryzae.

Recently, the incidence of invasive fungal infections has significantly increased. Candida albicans (C. albicans) is the most common opportunistic fungal pathogen that infects humans. The limited number of available antifungal agents and the emergence of drug resistance pose difficulties to treatment, thus new antifungals are urgently needed. Through their functions in DNA replication, DNA repair and transcription, histone acetyltransferases (HATs) and histone deacetylases (HDACs) perform essential functions relating to growth, virulence, drug resistance and stress responses of C. albicans. Here, we summarize the physiological and pathological functions of HATs/HDACs, potential antifungal targets and underlying antifungal compounds that impact histone acetylation and deacetylation. We anticipate this review will stimulate the identification of new HAT/HDAC-related antifungal targets and antifungal agents.

This review summarizes and highlights the latest advances of histone acetylation dynamics in various systemic and environment-responsive signaling pathways in plants., As sessile organisms, plants face versatile environmental challenges and require proper responses at multiple levels for survival. Epigenetic modification of DNA and histones is a conserved gene-regulatory mechanism and plays critical roles in diverse aspects of biological processes, ranging from genome defense and imprinting to development and physiology. In recent years, emerging studies have revealed the interplay between signaling transduction pathways, epigenetic modifications, and chromatin cascades. Specifically, histone acetylation and deacetylation dictate plant responses to environmental cues by modulating chromatin dynamics to regulate downstream gene expression as signaling outputs. In this review, we summarize current understandings of the link between plant signaling pathways and epigenetic modifications with a focus on histone acetylation and deacetylation.

Robust and reproducible protocols to efficiently reprogram adult canine cells to induced pluripotent stem cells are still elusive. Somatic cell reprogramming requires global chromatin remodeling that is finely orchestrated spatially and temporally. Histone acetylation and deacetylation are key regulators of chromatin condensation, mediated by histone acetyltransferases and histone deacetylases (HDACs), respectively. HDAC inhibitors have been used to increase histone acetylation, chromatin accessibility, and somatic cell reprogramming in human and mice cells. We hypothesized that inhibition of HDACs in canine fibroblasts would increase their reprogramming efficiency by altering the epigenomic landscape and enabling greater chromatin accessibility. We report that a combined treatment of panobinostat (LBH589) and vitamin C effectively inhibits HDAC function and increases histone acetylation in canine embryonic fibroblasts in vitro, with no significant cytotoxic effects. We further determined the effect of this treatment on global chromatin accessibility via Assay for Transposase-Accessible Chromatin using sequencing. Finally, the treatment did not induce any significant increase in cellular reprogramming efficiency. Although our data demonstrate that the unique epigenetic landscape of canine cells does not make them amenable to cellular reprogramming through the proposed treatment, it provides a rationale for a targeted, canine-specific, reprogramming approach by enhancing the expression of transcription factors such as CEBP.

Multiple myeloma (MM) is a biologically heterogenic disease with adequate wide spectrum of chromosomal, genetic and epigenetic changes. Epigenetic modifications can influence gene activity without changing the DNA sequence. There are biochemical modifications that include DNA methylation and post-translational modification of histone proteins (histone methylation, histone acetylation and deacetylation), that play an important role in the pathogenesis of MM. Epigenetic modifications are mediated through very important specialized enzymatic molecules, e.g. DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TET), histone acetyltransferases (HATs) and histone deacetylases (HDACs). In a complex machinery, specific of micro-RNA molecules contribute to epigenetic processes. Not only in myeloma genesis, but epigenetics influences a drug resistance and prognosis of patients with MM as well.

Thymoquinone is a natural product known for its anticancer activity. Preclinical studies indicated numerous mechanisms of action by which thymoquinone exerts its effects on cancer cells. Recent evidence has indicated that thymoquinone can modulate epigenetic machinery, like modifying histone acetylation and deacetylation, DNA methylation and demethylation, which are among the major epigenetic changes that can contribute to carcinogenesis. Moreover, thymoquinone can alter the genetic expression of various noncoding RNAs, such as miRNA and lncRNA, which are the key parts of cellular epigenetics. This review focuses on cellular epigenetic systems, epigenetic changes responsible for cancer and the counteraction of thymoquinone to target epigenetic challenges, which might be among the mechanisms of the thymoquinone effect in cancer cells.

BACKGROUND This study aimed to identify the pharmacological targets and mechanisms of action of the traditional Chinese medicine, formononetin, in the treatment of Alzheimer's disease (AD) using network pharmacological analysis. MATERIAL AND METHODS Targets of AD were obtained by using DisGeNET gene discovery platform, the herbal ingredients target (HIT) database, the SuperPred, and the SwissTargetPrediction compound target prediction platforms. Pathogenic and therapeutic targets were imported to the STRING biological database, and Cytoscape network integration software was used to construct component-target and disease-target interaction networks. Core targets were identified by topological analysis and were further tested to identify the biological processes and signaling pathways. RESULTS Seven key target genes for formononetin in the treatment of patients with AD were identified, including estrogen receptor alpha (ESR1), peroxisome proliferator-activated receptor gamma (PPARG), tumor protein p53 (TP53), sirtuin 1 (SIRT1), tumor necrosis factor (TNF), cytochrome P450 19A1 (CYP19A1), and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2). The biological processes included hormone metabolism, regulation of nucleoside, nucleotide and nucleic acid metabolism, apoptosis, energy pathways, metabolism, cell communication, and signal transduction. The signaling pathways included histone acetylation and deacetylation (HDAC) class I, regulation of p38-alpha/beta, p38 mitogen-activated protein kinase (MAPK) signaling pathway, bone morphogenetic protein (BMP) receptor signaling, interleukin-1 (IL1) mediated signaling events, the tumor necrosis factor (TNF) receptor signaling pathway, and cytoplasmic and nuclear Smad2/3 signaling. CONCLUSIONS Pharmacological network analysis was used to identify the gene targets and mechanisms of formononetin treatment in patients with AD.

The equilibrium between histone acetylation and deacetylation plays an important role in cancer initiation and progression. The histone deacetylases (HDACs) are a class of key regulators of gene expression that enzymatically remove an acetyl moiety from acetylated lysine e-amino groups on histone tails. Therefore, HDAC inhibitors have recently emerged as a promising strategy for cancer therapy and several pan-HDAC inhibitors have globally been approved for clinical use. In the present study, we designed and synthesized a series of substituted indole-based hydroxamic acid derivatives that exhibited potent anti-proliferative activities in various tumor cell lines. Among the compounds tested, compound 4o, was found to be among the most potent in the inhibition of HDAC1 (half maximal inhibitory concentration, IC50 = 1.16 nM) and HDAC6 (IC50 = 2.30 nM). It also exhibited excellent in vitro anti-tumor proliferation activity. Additionally, compound 4o effectively increased the acetylation of histone H3 in a dose-dependent manner and inhibited cell proliferation by inducing cell cycle arrest and apoptosis. Moreover, compound 4o remarkably blocked colony formation in HCT116 cancer cells. Based on its favorable in vitro profile, compound 4o was further evaluated in an HCT116 xenograft mouse model, in which it demonstrated better in vivo efficacy than the clinically used HDAC inhibitor, suberanilohydroxamic acid. Interestingly, compound 4k was found to have a preference for the inhibition of HDAC6, with IC50 values of 115.20 and 5.29 nM against HDAC1 and HDAC6, respectively.

In eukaryotes, dynamic chromatin states are closely related to changes in gene expression. Epigenetic modifications help plants adapt to their ever-changing environment by modulating gene expression via covalent modification at specific sites on DNA or histones. Sugars provide energy, but also function as signaling molecules to control plant growth and development. Various epigenetic modifications participate in sensing and transmitting sugar signals. Here we summarize recent progress in uncovering the epigenetic mechanisms involved in sugar signal transduction, including histone acetylation and deacetylation, histone methylation and demethylation, and DNA methylation. We also highlight changes in chromatin marks when crosstalk occurs between sugar signaling and the light, temperature, and phytohormone signaling pathways, and describe potential questions and approaches for future research.

Histone acetyltransferases are responsible for histone acetylation, while histone deacetylases (HDACs) counteract histone acetylation. An unbalanced dynamic between histone acetylation and deacetylation may lead to aberrant chromatin landscape and chromosomal function. HDAC2, a member of class I HDAC family, serves a crucial role in the modulation of cell signaling, immune response and gene expression. HDAC2 has emerged as a promising therapeutic target for liver disease by regulating gene transcription, chromatin remodeling, signal transduction and nuclear reprogramming, thus receiving attention from researchers and clinicians. The present review introduces biological information of HDAC2 and its physiological and biochemical functions. Secondly, the functional roles of HDAC2 in liver disease are discussed in terms of hepatocyte apoptosis and proliferation, liver regeneration, hepatocellular carcinoma, liver fibrosis and non‑alcoholic steatohepatitis. Moreover, abnormal expression of HDAC2 may be involved in the pathogenesis of liver disease, and its expression levels and pharmacological activity may represent potential biomarkers of liver disease. Finally, research on selective HDAC2 inhibitors and non‑coding RNAs relevant to HDAC2 expression in liver disease is also reviewed. The aim of the present review was to improve understanding of the multifunctional role and potential regulatory mechanism of HDAC2 in liver disease.

Histone acetylation is an important, reversible post-translational protein modification and a hallmark of epigenetic regulation. However, little is known about the dynamics of this process, due to the lack of analytical methods that can capture site-specific acetylation and deacetylation reactions. We present a new approach that combines metabolic and chemical labeling (CoMetChem) using uniformly 13C-labeled glucose and stable isotope labeled acetic anhydride. Thereby, chemically equivalent, fully acetylated histone species are generated enabling accurate relative quantification of site-specific lysine acetylation in tryptic peptides using high-resolution mass spectrometry. We show that CoMetChem enables site-specific quantification of the incorporation or loss of lysine acetylation over time, allowing the determination of reaction rates for acetylation and deacetylation. Thus, the CoMetChem methodology provides a comprehensive description of site-specific acetylation dynamics.

Sirtuins are the class III of histone deacetylases that depend on nicotinamide adenine dinucleotide for their activity. Sirtuins can influence the progression of neurodegenerative disorders by switching between deacetylation and acetylation processes. Histone acetylation occurs when acetyl groups are added to lysine residues on the N-terminal part of histone proteins. Deacetylation, on the other hand, results in the removal of acetyl groups. Pharmacological modulation of sirtuin activity has been shown to influence various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. In this review, mechanistic perspective of sirtuins has been discussed in anti-inflammatory, antiapoptotic, and neuroprotective effects in various disorders. We have discussed the structure, neurobiology, and physiology of sirtuins in neurodegenerative disease. Recent preclinical and clinical studies and their outcome have also been elucidated. The aim of this review is to fill in the gaps in our understanding of sirtuins' role in histone acetylation and deacetylation in all neurodegenerative diseases. Here, we emphasized on reviewing all the studies carried out in various labs depicting the role of sirtuin modulators in neuroprotection and highlighted the ideas that can be considered for future perspectives. Taken together, sirtuins may serve as a promising therapeutic target for the treatment of neurodegenerative disorders.

Persistent symptoms of depression indicate the adaptive involvement of stable molecules in the brain that may be manifested at the level of chromatin remodeling, such as histone acetylation. Former studies have identified alterations in histone acetylation and deacetylation in several animal models about depression. However, the specific histone deacetylases related with depression are needed to be explored. Here, social avoidance behaviors, anxiety-, and depression-like behaviors were all found in mice suffered from chronic social defeat stress. Moreover, we also discovered that the amount of the class II histone deacetylase, HDAC7 rather than HDAC2, was significantly decreased in the nucleus accumbens of defeated mice, which suggested that HDAC7 might be a crucial histone deacetylase in a chronic social defeat stress model. Our data showed that the depressive-like behaviors induced by chronic social defeat stress were associated with HDAC7 reduction in nucleus accumbens. HDAC7 might be a promising therapeutic target for depression.

Reversible histone acetylation and deacetylation play crucial roles in modulating light-regulated gene expression during seedling development. However, it remains largely unknown how histone-modifying enzymes interpose within the molecular framework of light signaling network. In this study, we show that AtHDA15 positively regulates photomorphogenesis by directly binding to COP1, a master regulator in the repression of photomorphogenesis. hda15 T-DNA knock-out and RNAi lines exhibited light hyposensitivity with reduced HY5 and PIF3 protein levels leading to long hypocotyl phenotypes in the dark while its overexpression leads to increased HY5 concentrations and short hypocotyl phenotypes. In vivo and in vitro binding assays show that HDA15 directly interacts with COP1 inside the nucleus modulating COP1’s repressive activities. As COP1 is established to act within the nucleus to regulate specific transcription factors associated with growth and development in skotomorphogenesis, the direct binding by HDA15 is predicted to abrogate activities of COP1 in the presence of light and modulate its repressive activities in the dark. Our results append the mounting evidence for the role of HDACs in post-translational regulation in addition to their well-known histone modifying functions.

Skeletal muscle is the largest metabolic organ in the human body and is able to rapidly adapt to drastic changes during exercise. Histone acetyltransferases (HATs) and histone deacetylases (HDACs), which target histone and non-histone proteins, are two major enzyme families that control the biological process of histone acetylation and deacetylation. Balance between these two enzymes serves as an essential element for gene expression and metabolic and physiological function. Genetic KO/TG murine models reveal that HDACs possess pivotal roles in maintaining skeletal muscles’ metabolic homeostasis, regulating skeletal muscles motor adaptation and exercise capacity. HDACs may be involved in mitochondrial remodeling, insulin sensitivity regulation, turn on/off of metabolic fuel switching and orchestrating physiological homeostasis of skeletal muscles from the process of myogenesis. Moreover, many myogenic factors and metabolic factors are modulated by HDACs. HDACs are considered as therapeutic targets in clinical research for treatment of cancer, inflammation, and neurological and metabolic-related diseases. This review will focus on physiological function of HDACs in skeletal muscles and provide new ideas for the treatment of metabolic diseases.

Among all the major environmental challenges, drought stress causes considerable damage to plant growth and agricultural productivity. Drought stress directly promotes the accumulation of abscisic acid (ABA) via the activation of genes that encode enzymes involved in ABA biosynthesis, which protect the plant against water-limiting conditions. At the same time, the expression of genes that encode ABA-hydroxylases that inactivate the newly synthesized ABA, is repressed by drought stress. These phenomena occur through epigenetic modifications via the reversible processes of histone acetylation and deacetylation, also known as chromatin remodeling, which is an important regulatory mechanism that responds to various environmental stresses. Recently, we had reported that the chromatin remodeling complex HDA9-PWR-ABI4 promotes the development of drought tolerance through the deacetylation of CYP707A1/2 genes that encode the major enzymes involved in ABA catabolism. Here, we discuss the role of HDA9 and PWR in regulating drought stress by modulating the acetylation status of the CYP707A genes.

Parasitoids are insects that use other insects as hosts. They sabotage host cellular and humoral defences to promote the survival of their offspring by injecting viruses and venoms along with their eggs. Many pathogens and parasites disrupt host epigenetic mechanisms to overcome immune system defences, and we hypothesized that parasitoids may use the same strategy. We used the ichneumon waspPimpla turionellaeas a model idiobiont parasitoid to test this hypothesis, with pupae of the greater wax mothGalleria mellonellaas the host. We found that parasitoid infestation involves the suppression of host immunity-related effector genes and the modulation of host genes involved in developmental hormone signalling. The transcriptional reprogramming of host genes following the injection of parasitoid eggs was associated with changes in host epigenetic mechanisms. The introduction of parasitoids resulted in a transient decrease in host global DNA methylation and the modulation of acetylation ratios for specific histones. Genes encoding regulators of histone acetylation and deacetylation were mostly downregulated in the parasitized pupae, suggesting that parasitoids can suppress host transcription. We also detected a strong parasitoid-specific effect on host microRNAs regulating gene expression at the post-transcriptional level. Our data therefore support the hypothesis that parasitoids may favour the survival of their offspring by interfering with host epigenetic mechanisms to suppress the immune system and disrupt development.

Hippo signalling pathway that is evolutionarily conserved affects diver’s pathology and physiology processes, including tissue repair, wound healing, tissue size and tissue regeneration. Epigenetic changes are post-translational modifications in DNA proteins and histones. Epigenetic changes including histone acetylation and deacetylation, miRNAs dysregulation, and aberrant DNA methylation, inflammatory genes actives abnormal in Hippo signaling pathway. Using some treatments, including Histone Deacetylases (HDACs), herbal composition, siRNAs and long non-coding RNA (lncRNA) for suppressing cancer cells by targeting Hippo pathways, may open new views in cancer target therapy fields. The aim of this review study is firstly to demonstrate the importance of Hippo signalling and its association with epigenetic changes in cancer and then to demonstrate progress in targeting Hippo signalling in cancer therapy.

Neurodevelopment is a highly complex process composed of several carefully regulated events starting from the proliferation of neuroepithelial cells and culminating with and refining of neural networks and synaptic transmission. Improper regulation of any of these neurodevelopmental events often results in severe brain dysfunction. Accumulating evidence indicates that epigenetic modifications of chromatin play a key role in neurodevelopmental regulation. Among these modifications are histone acetylation and deacetylation, which control access of transcription factors to DNA, thereby regulating gene transcription. Histone deacetylation, which restricts access of transcription factor repressing gene transcription, involves the action of members of a family of 18 enzymes, the histone deacetylases (HDAC), which are subdivided in 4 subgroups. This review focuses on the Group 1 HDACs – HDAC 1, 2, 3, and 8. Although much of the evidence for HDAC involvement in neurodevelopment has come from the use of pharmacological inhibitors, because these agents are generally nonselective with regard to their effects on individual members of the HDAC family, this review is limited to evidence garnered from the use of molecular genetic approaches. Our review describes that Class I HDACs play essential roles in all phases of neurodevelopment. Modulation of the activity of individual HDACs could be an important therapeutic approach for neurodevelopmental and psychiatric disorders.

Drug use leads to addiction in some individuals, but the underlying brain mechanisms that control the transition from casual drug use to an intractable substance use disorder (SUD) are not well understood. Gene x environment interactions such as the frequency of drug use and the type of substance used likely to promote maladaptive plastic changes in brain regions that are critical for controlling addiction-related behavior. Epigenetics encompasses a broad spectrum of mechanisms important for regulating gene transcription that are not dependent on changes in DNA base pair sequences. This review focuses on the proteins and complexes contributing to epigenetic modifications in the nucleus accumbens (NAc) following drug experience. We discuss in detail the three major mechanisms: histone acetylation and deacetylation, histone methylation, and DNA methylation. We discuss how drug use alters the regulation of the associated proteins regulating these processes and highlight how experimental manipulations of these proteins in the NAc can alter drug-related behaviors. Finally, we discuss the ways that histone modifications and DNA methylation coordinate actions by recruiting large epigenetic enzyme complexes to aid in transcriptional repression. Targeting these multiprotein epigenetic enzyme complexes - and the individual proteins that comprise them - might lead to effective therapeutics to reverse or treat SUDs in patients.

Aims Histone acetylation and deacetylation are two histone posttranslational modifications that are usually controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Although HATs or HDACs Inhibitors could relieve pain hypersensitivities in chronic pain animal models, it is not clear on the expression of global histone acetylation in the dorsal root ganglion (DRG) or spinal dorsal horn in chronic pain conditions. Main methods A spinal nerve ligation (SNL)-induced neuropathic pain model and a complete Freund's adjuvant (CFA)-induced inflammatory pain model in rats were used to examine the expression of total acetyl-histone H3 (AcH3) and total acetyl-histone H4 (AcH4) by immunofluorescence or western blot. Key findings AcH3 and AcH4 not only localized in neuronal nuclei, but also in nuclei of glial cells in the DRG. Unilateral SNL induced the increase of AcH3 and AcH4 expression in the injured lumbar 5 (L5) DRG, but not in the uninjured L5 DRG or the spinal dorsal horn, while unilateral intraplantar injection of CFA increased AcH3 and AcH4 expression in the ipsilateral L4/5 spinal dorsal horn, but not in the L4/5 DRG. Significance These results provide morphological evidence for global histone acetylation expression in the DRG and spinal cord and indicate the differential expression in the DRG and spinal dorsal horn in different chronic pain models. More precise epigenetic mechanisms of histone acetylation on the target genes need to be revealed.

Inflammation supports the progression of alcohol-related organ injury. Recent research findings have linked ethanol exposure to changes in histone acetylation and deacetylation in the brain and in peripheral tissues, leading to ethanol-dependence related damage. One of the mechanisms that has been shown to play a major role during inflammation is the cannabinoid system. Previous research has demonstrated that ethanol can modulate cannabinoid receptors' functions. Our lab has shown that the G protein-coupled receptor (GPR55), a novel cannabinoid receptor, is upregulated in binge drinkers and in cells treated acutely with ethanol. Additionally, our group has also uncovered that chronic ethanol exposure leads to an increase in histone modifications, such as acetylation. However, the regulatory mechanism of GPR55 within the immune system under the influence of ethanol is poorly understood. Since changes in histone modifications might lead to changes in gene expression, we hypothesize that the mechanism of ethanol-induced upregulation of GPR55 is linked to epigenetic changes on histone proteins. Taking into account previous findings from our lab, the goal of the present study was to determine whether there is any relevant association between histone hyperacetylation and the regulation of the novel cannabinoid receptor GPR55 in monocyte-derived dendritic cells (MDDCs) of human origin treated acutely with ethanol. Therefore, monocytes were isolated from buffy coats and allowed to differentiate into MDDCs. The cells were treated with ethanol for 24 h, harvested, fixed, and stained with antibodies against GPR55. As expected, based on previous findings, confocal microscopy showed that ethanol exposure increases GPR55 expression. In order to demonstrate the correlation between histone acetylation and GPR55 expression regulation, the cells were treated with ethanol, harvested, and then the chromatin was extracted and fractionated for chromatin immunoprecipitation (ChIP) assay, followed by real-time qPCR for the analysis of DNA fragments. The results showed an enrichment of the histone modification H4K12ac in the GPR55 gene of MDDCs treated with ethanol. Furthermore, siRNA against the histone acetyltransferase Tip60 (responsible for the acetylation of H4K12) resulted in a downregulation of GPR55. In conjunction, these results indicate that in the presence of ethanol, the upregulation of GPR55 expression is accompanied by H4K12 acetylation, which might have a significant effect in the ability of this innate immune system's cells to cope with cellular stress induced by ethanol. However, the causality of ethanol regulation of H4K12ac in GPR55 expression changes still lacks further elucidation; therefore, additional experimental approaches to confirm a significant causality between H4K12 acetylation and ethanol regulation of GPR55 are currently undergoing in our lab.

BACKGROUND The modification of histone acetylation and deacetylation is the most important mechanism of chromatin remodeling. These modifications are a subset of epigenetic alterations which affect tumorigenesis and progression through changes in gene expression and cell growth. Results of histone modification studies prompted us to explore the therapeutic and prognostic significance of histone deacetylase 3 (HDAC3) expression in patients with breast cancer. MATERIAL AND METHODS Immunohistochemical (IHC) staining was used to detect HDAC3 expression in a tissue microarray (TMA) that included 145 patients diagnosed with invasive ductal breast carcinoma. IHC scoring was used to evaluate the staining intensity and the proportion of positive cells. RESULTS HDAC3 expression was significantly correlated with estrogen receptor (ER)-negative expression (P=0.036) and progesterone receptor (PR)-negative expression (P=0.024). Additionally, HDAC3 expression was significantly positively correlated with human epidermal growth factor 2 (HER2) overexpression (P=0.037). Our study also indicated that high expression of HDAC3 was more frequently observed in breast tumors with PT2 classification (74%) versus PT1 (50.0%) and PT3 (71.4%) (P=0.040). Furthermore, HDAC3 was correlated with clinical stage II (P=0.046). Univariate and multivariate survival analyses showed that high expression of HDAC3 was correlated with poor overall survival (OS) (P=0.029 and P=0.033, respectively) in patients without lymph node involvement. CONCLUSIONS High HDAC3 expression is closely correlated with ER-negative expression, PR-negative expression, HER2 overexpression, PT stage, and clinical stage of breast tumors. HDAC3 may be an appropriate prognostic indicator in patients with invasive ductal breast cancer.

Histone acetylation and deacetylation correlate with diverse biological phenomena through gene transcription. Histone deacetylases (HDACs) regulate deacetylation of histones and other proteins. However, as a member of the HDAC family, HDAC8 function during neurodevelopment is currently unknown. Therefore, we investigated HDAC8 function during neurodevelopment by examining embryoid body (EB) formation in P19 cells. HDAC8-selective inhibitor (NCC-149) (HDAC8i)-treated cells showed smaller EBs than non-treated cells, as well as reduced expression levels of the neuronal marker, NeuN. Additionally, HDAC8i treatment led to inhibition of cellular proliferation by G2/M phase accumulation and downregulated cyclin A2 and cyclin B1 gene expression. Furthermore, two independent HDAC8 knockout cell lines were established by CRISPR-Cas9, which resulted in smaller EBs, similar to HDAC8i-treated cells. These results suggest that HDAC8 regulates neural differentiation by exerting control of EB formation.

The pathogenesis of systemic lupus erythematosus (SLE) is influenced by both genetic factors and epigenetic modifications; the latter is a result of exposure to various environmental factors. Epigenetic modifications affect gene expression and alter cellular functions without modifying the genomic sequences. CpG-DNA methylation, histone modifications, and miRNAs are the main epigenetic factors of gene regulation. In SLE, global and gene-specific DNA methylation changes have been demonstrated to occur in CD4+ T-cells. Moreover, histone acetylation and deacetylation inhibitors reverse the expression of multiple genes involved in SLE, indicating histone modification in SLE. Autoreactive T-cells and B-cells have been shown to alter the patterns of epigenetic changes in SLE patients. Understanding the molecular mechanisms involved in the pathogenesis of SLE is critical for the introduction of effective, target-directed and tolerated therapies. In this review, we summarize the recent findings that highlight the importance of epigenetic modifications and their mechanisms in SLE.

Histone deacetylases modulate the dynamic balance of histone acetylation and deacetylation in cells, which participate in epigenetic regulations. Accumulated evidence has demonstrated that histone deacetylases are associated with angiogenesis, cell proliferation and survival in a variety of human cancers. However, the expression and distinct prognostic value of histone deacetylases in ovarian cancer have not been well elucidated. In the present study, we collected the overall survival (OS), progress free survival (PFS), and histone deacetylases (HDAC1-11) mRNA expression in ovarian cancer from the Kaplan-Meier plotter online database. We investigated the relationship between histone deacetylases mRNA level and the clinicopathological parameters of the ovarian cancer patients, such as histology subtypes, clinical stages, grades and TP53 mutation. Our analysis data showed that over-expression of HDAC1, HDAC2, HDAC4, HDAC5 and HDAC11 were correlated to poor overall survival and unfavorable progress free survival in all ovarian cancer patients. Notably, the higher level of HDAC11 was associated with the worse OS and PFS for serous/ stage III+IV/ grade III/ TP53 mutation ovarian cancer patients. In conclusion, HDACs may play a crucial role in the prognosis of ovarian cancer, but it is worth noting that HDAC11 may be a biomarker for poor prognosis in ovarian cancer patients.

MYCN Proto-Oncogene, BHLH Transcription Factor (MYCN) has been one of the most studied genes in neuroblastoma. It is known for its oncogenetic mechanisms, as well as its role in the prognosis of the disease and it is considered one of the prominent targets for neuroblastoma therapy. In the present work, we attempted to review the literature, on the relation between MYCN and neuroblastoma from all possible mechanistic sites. We have searched the literature for the role of MYCN in neuroblastoma based on the following topics: the references of MYCN in the literature, the gene’s anatomy, along with its transcripts, the protein’s anatomy, the epigenetic mechanisms regulating MYCN expression and function, as well as MYCN amplification. MYCN plays a significant role in neuroblastoma biology. Its functions and properties range from the forming of G-quadraplexes, to the interaction with miRNAs, as well as the regulation of gene methylation and histone acetylation and deacetylation. Although MYCN is one of the most primary genes studied in neuroblastoma, there is still a lot to be learned. Our knowledge on the exact mechanisms of MYCN amplification, etiology and potential interventions is still limited. The knowledge on the molecular mechanisms of MYCN in neuroblastoma, could have potential prognostic and therapeutic advantages.

T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables TH17 cell differentiation remains elusive. Here we reveal that TGFβ enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGFβ controls TH17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating TH17-related diseases.

The most recent outcomes about the transcription factors and transcription complexes mediated auxin signaling pathway by the histone acetylation and deacetylation. The phytohormone auxin, is required to regulate its accumulation spatiotemporally and responses to orchestrate various developmental levels in plants. Histone acetylation and deacetylation modulate auxin biosynthesis, its distribution and accumulation. In the absence of auxin, histone deacetylase represses the expression of auxin-responsive genes. Various transcription factors and transcription complexes facilitate the proper regulation of auxin signaling pathway genes. The primary and lateral root development, promotion of flowering and initiation of seed germination are all regulated by auxin-mediated histone acetylation and deacetylation. These findings conclude the auxin mode of action, which is mediated by histone acetylation and deacetylation, and associated phenotypic responses in plants, along with the underlying mechanism of these modifications.

Reversible protein acetylation, one of the key types of post-translational modifications, is composed of histone acetylation and deacetylation, which is typically catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) respectively. Herein, a label-free fluorescent method has been established for the homogeneous bioassay of HAT/HDAC activity and respective inhibitors. The proposed approach is primarily based on the electrostatic interaction between G-quadruplexes (G4s) and acetylation-related peptides, which results in marked change of fluorescent intensity of G4/Thioflavin T (ThT) complexes. This HAT (p300) activity assay is exceedingly sensitive and selective, with a linear range from 0.1 to 120nM and a detection limit of 0.05nM. Moreover, this biosensor is feasible to detect the HDAC (Sirt1) activity with a linear range from 1 to 450nM and a detection limit of 1nM. The potency of this assay is further demonstrated by detecting HAT/HDAC activity in cell lysates and evaluating HAT and HDAC-targeted inhibitors, C464 and EX 527, respectively. The proposed assay is convenient, label-free and cost-efficient, which is promising for HAT/HDAC-targeted epigenetic research and pharmaceutical development.

Histone acetylation is an evolutionarily conserved epigenetic mechanism of eukaryotic gene regulation which is tightly controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). In insects, life-history traits such as longevity and fecundity are severely affected by the suppression of HAT/HDAC activity, which can be achieved by RNA-mediated gene silencing or the application of chemical inhibitors. We used both experimental approaches to investigate the effect of HAT/HDAC inhibition in the pea aphid (Acyrthosiphon pisum) a model insect often used to study complex life-history traits. The silencing of HAT genes (kat6b, kat7, and kat14) promoted survival or increased the number of offspring, whereas targeting rpd3 (HDAC) reduced the number of viviparous offspring but increased the number of premature nymphs, suggesting a role in embryogenesis and eclosion. Specific chemical inhibitors of HATs/HDACs showed a remarkably severe impact on life-history traits, reducing survival, delaying development, and limiting the number of offspring. The selective inhibition of HATs and HDACs also had opposing effects on aphid body weight. The suppression of HAT/HDAC activity in aphids by RNA interference or chemical inhibition revealed similarities and differences compared to the reported role of these enzymes in other insects. Our data suggest that gene expression in A. pisum is regulated by multiple HATs/HDACs, as indicated by the fitness costs triggered by inhibitors that suppress several of these enzymes simultaneously. Targeting multiple HATs or HDACs with combined effects on gene regulation could, therefore, be a promising approach to discover novel targets for the management of aphid pests.

In plants, reversible histone acetylation and deacetylation play a crucial role in various biological activities, including development and the response to environmental stress. Histone deacetylation, which is generally associated with gene silencing, is catalyzed by multiple histone deacetylases (HDACs). Our understanding of HDAC function in plant development has accumulated from molecular genetic studies in Arabidopsis thaliana. By contrast, how HDACs contribute to the development of rice (Oryza sativa) is poorly understood and no rice mutants of HDAC have been reported. Here we have characterized a new rice mutant showing semi-dwarfism, which we named dwarf with slender leaf1 (dsl1). The mutant showed pleiotropic defects in both vegetative and reproductive development; for example, dsl1 produced short and narrow leaves, accompanied with a reduction in the number and size of vascular bundles. The semi-dwarf phenotype was due to suppression of the elongation of some culm (stem) internodes. Interestingly, despite this suppression of the upper internodes, the elongation and generation of lower internodes were slightly enhanced. Inflorescence and spikelet development were also affected by the dsl1 mutation. Some of the observed morphological defects were related to a reduction in cell numbers, in addition to reduced cell division in leaf primordia revealed by in situ hybridization analysis, suggesting the possibility that DSL1 is involved in cell division control. Gene cloning revealed that DSL1 encodes an HDAC belonging to the Reduced potassium dependence3/Histone Deacetylase1 (RPD3/HDA1) family. Collectively, our study shows that the HDAC DSL1 plays diverse and important roles in development in rice.

An increasingly number of women of all age groups are affected by cancer, despite substantial progress in our understanding of cancer pathobiology, the underlying genomic alterations and signaling cascades, and cellular-environmental interactions. Though our understanding of women’s cancer is far more complete than ever before, there is no comprehensive model to explain the reasons behind the increased incidents of certain reproductive cancer among older as well as younger women. It is generally suspected that environmental and life-style factors affecting hormonal and growth control pathways might help account for the rise of women’s cancers in younger age, as well, via epigenetic mechanisms. Epigenetic regulators play an important role in orchestrating an orderly coordination of cellular signals in gene activity in response to upstream signaling and/or epigenetic modifiers present in a dynamic extracellular milieu. Here we will discuss the broad principles of epigenetic regulation of DNA methylation and demethylation, histone acetylation and deacetylation, and RNA methylation in women’s cancers in the context of gene expression, hormonal action, and the EGFR family of cell surface receptor tyrosine kinases. We anticipate that a better understanding of the epigenetics of women’s cancers may provide new regulatory leads and further fuel the development of new epigenetic biomarkers and therapeutic approaches.

Histone acetylation and deacetylation play essential roles in eukaryotic gene regulation. HD2 (HD-tuins) proteins were previously identified as plant-specific histone deacetylases. In this study, we investigated the function of the HDT1 gene in the formation of stem vascular tissue in Arabidopsis thaliana. The height and thickness of the inflorescence stems in the hdt1 mutant was lower than that of wild-type plants. Paraffin sections showed that the cell number increased compared to the wild type, while transmission electron microscopy showed that the size of individual tracheary elements and fiber cells significantly decreased in the hdt1 mutant. In addition, the cell wall thickness of tracheary elements and fiber cells increased. We also found that the lignin content in the stem of the hdt1 mutants increased compared to that of the wild type. Transcriptomic data revealed that the expression levels of many biosynthetic genes related to secondary wall components, including cellulose, lignin biosynthesis, and hormone-related genes, were altered, which may lead to the altered phenotype in vascular tissue of the hdt1 mutant. These results suggested that HDT1 is involved in development of the vascular tissue of the stem by affecting cell proliferation and differentiation.

Oncogenic viruses are one of the most important causes of cancer worldwide. The pathogens contribute to the establishment of human malignancies by affecting various cellular events. Epigenetic mechanisms, such as histone modification methylation/demethylation, are one of the most critical events manipulated by oncogenic viruses to drive tumorigenesis. Histone modifications are mediated by histone acetylation and deacetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Dysregulation of HDACs activity affects viral tumorigenesis in several ways, such as manipulating tumor suppressor and viral gene expression. The present review aims to describe the vital interactions between both cancer-caused/associated viruses and the HDAC machinery, particularly by focusing on those viruses involved in gastrointestinal tumors, as some of the most common viral-mediated cancers.

Despite the rapid development of CRISPR/Cas9-mediated gene editing technology, the gene editing potential of CRISPR/Cas9 is hampered by low efficiency, especially for clinical applications. One of the major challenges is that chromatin compaction inevitably limits the Cas9 protein access to the target DNA. However, chromatin compaction is precisely regulated by histone acetylation and deacetylation. To overcome these challenges, we have comprehensively assessed the impacts of histone modifiers such as HDAC (1–9) inhibitors and HAT (p300/CBP, Tip60 and MOZ) inhibitors, on CRISPR/Cas9 mediated gene editing efficiency. Our findings demonstrate that attenuation of HDAC1, HDAC2 activity, but not other HDACs, enhances CRISPR/Cas9-mediated gene knockout frequencies by NHEJ as well as gene knock-in by HDR. Conversely, inhibition of HDAC3 decreases gene editing frequencies. Furthermore, our study showed that attenuation of HDAC1, HDAC2 activity leads to an open chromatin state, facilitates Cas9 access and binding to the targeted DNA and increases the gene editing frequencies. This approach can be applied to other nucleases, such as ZFN and TALEN.

Chemotherapy resistance is a rising concern in Gastric Cancer (GC) and has led to the investigation of various cellular compounds. Α functional equilibrium of histone acetylation and deacetylation was discovered in all cells, regulated by Histone Acetyltransferases and Deacetylases (HDACs), controlling chromatin coiling status and changing gene expression appropriately. In accordance with recent research, this equilibrium can be dysregulated in cancer cells aiding in the process of carcinogenesis and tumor progression by altering histone and non-histone proteins affecting gene expression, cell cycle control, differentiation, and apoptosis in various malignancies. In addition, increased HDAC expression in GC cells has been associated with increased stage, tumor invasion, nodal metastases, increased distant metastatic potential, and decreased overall survival. HDAC inhibitors could be used as treatment regimens for GC patients and could develop important synergistic interactions with chemotherapy drugs. The aim of this article is to review the molecular identity and mechanism of action of HDAC inhibitors, as well as highlight their potential utility as anti-cancer agents in GC.

Bone cells must constantly respond to hormonal and mechanical cues to change gene expression programs. Of the myriad of epigenomic mechanisms used by cells to dynamically alter cell type-specific gene expression, histone acetylation and deacetylation has received intense focus over the past two decades. Histone deacetylases (HDACs) represent a large family of proteins with a conserved deacetylase domain first described to deacetylate lysine residues on histone tails. It is now appreciated that multiple classes of HDACs exist, some of which are clearly misnamed in that acetylated lysine residues on histone tails is not the major function of their deacetylase domain. Here, we will review the roles of proteins bearing deacetylase domains in bone cells, focusing on current genetic evidence for each individual HDAC gene. While class I HDACs are nuclear proteins whose primary role is to deacetylate histones, class IIa and class III HDACs serve other important cellular functions. Detailed knowledge of the roles of individual HDACs in bone development and remodeling will set the stage for future efforts to specifically target individual HDAC family members in the treatment of skeletal diseases such as osteoporosis.

Histone acetylation and deacetylation play an important role in plant growth and development by chromatin modifications. Regulation of histone acetylation and deacetylation is controlled by histone acetyltransferases and histone deacetylases (HDACs) in different tissues and development stages. Knowledge of the importance of genome stability, transcriptional regulation, development and response to stress has been obtained from the model plant Arabidopsis. However, little information on biological functions and development or stress-related HDAC genes is available in tomato. In this study, nine tomato histone deacetylase genes of the RPD3/HDA1 subfamily, from SlHDA1-SlHDA9, were characterized to encode histone deacetylase proteins that share high similarity of protein sequences and conserved domains with those of known plant HDACs. These HDAC genes have been further subdivided into four groups, namely Class I, Class II, Class III and Class IV based on phylogenetic analysis. Quantitative RT-PCR analysis revealed that the nine SlHDAC genes were expressed in all tissues with different transcript abundance and exhibited different tissue-specific expression profiles, suggesting that they may have crucial and diverse roles in tomato growth and development. Varying degrees of induction were detected in the transcript levels of these SlHDACs under various abiotic stresses including NaCl, dehydration, and high/low temperature. These nine SlHDACs were induced by the above stresses with differential/similar induction levels. Overall, this study provides valuable information for further exploring the regulation of HDAC genes during tomato development and fruit ripening and in response to environmental stresses.

Diverse cellular functions, including tumor suppressor gene expression, DNA repair, cell proliferation and apoptosis, are regulated by histone acetylation and deacetylation. Histone deacetylases (HDACs) are enzymes involved in remodeling of chromatin by deacetylating the lysine residues. They play a pivotal role in epigenetic regulation of gene expression. Dysregulation of HDACs and aberrant chromatin acetylation and deacetylation have been implicated in the pathogenesis of various diseases, including cancer. Histone deacetylases have become a target for the development of drugs for treating cancer because of their major contribution to oncogenic cell transformation. Overexpression of HDACs correlates with tumorigenesis. Previous work showed that inhibition of HDACs results in apoptosis and the inhibition of cell proliferation in multiple cells. A significant number of HDAC inhibitors have been developed in the past decade. These inhibitors have strong anticancer effects in vitro and in vivo, inducing growth arrest, differentiation, and programmed cell death, inhibiting cell migration, invasion, and metastasis, and suppressing angiogenesis. In addition, HDAC-mediated deacetylation alters the transcriptional activity of nuclear transcription factors, including p53, E2F, c-Myc, and nuclear factor-κB, as well as the extracellular signal-regulated kinase1/2, phosphatidylinositol 3-kinase, Notch, and Wnt signaling pathways. This review highlights the role of HDACs in cancer pathogenesis and, more importantly, that HDACs are potential novel therapeutic targets.

Histone acetylation and deacetylation play crucial roles in the modification of chromatin structure and regulation of gene expression in eukaryotes. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) assist to maintain the balance of chromatin acetylation status. Previous studies showed that plant HDACs are key regulators involved in response to development and stresses. In this study, we examined the expression pattern and function of HDA705, a member of the RPD3/HDA1-type HDAC in rice. Overexpression of HDA705 in rice decreased ABA and salt stress resistance during seed germination. Delayed seed germination of HDA705 overexpression lines was associated with down-regulated expression of GA biosynthetic genes and up-regulation of ABA biosynthetic genes. Moreover, overexpression of HDA705 in rice enhanced osmotic stress resistance during the seedling stage. Our findings demonstrate that HDA705 may play a role in regulating seed germination and the response to abiotic stresses in rice.

The acetylation of histone tails, which relaxes compact chromatin structure and enhances the accessibility of DNA to regulatory proteins, has emerged as a key mechanism for regulating gene expression. These modifications in turn play critical roles in forming long-term memories. Chromatin immunoprecipitation (ChIP) experiments have enabled the identification of specific histone modifications and the genes most closely associated with active memory formation. Problematically, however, the majority of these studies analyze diverse populations of cell homogenates obtained from the gross dissection of large brain regions. The protocol outlined here uses methods to ascribe gene-specific histone modifications (via specific antibodies and RT-qPCR) to specific cell subtypes (via specific antibodies and cell sorting) in discrete memory-related brain regions (via microdissection) to more precisely identify the role of histone acetylation and deacetylation in cognitive neuroepigenetics.