Role Of Histone Acetylation Research Articles

Sodium butyrate modulates a methamphetamine-induced conditioned place preference.

Previous studies demonstrated that histone acetylation modulated the transcription of associated gene expression and thus contributed to the persistence of addictive behaviors and neuroplasticity. Nonetheless, the roles of histone acetylation in distinct phases of methamphetamine (METH)-induced conditioned place preference (CPP) remain unclear. The current study examines the effects of the histone deacetylases (HDACs) inhibitor sodium butyrate (NaB) on the acquisition, extinction, and reinstatement of METH-induced CPP in mice. Our results showed that 1 mg/kg METH induced CPP in mice after four conditioning sessions. METH-induced CPP was extinguished after three extinction training sessions and could be triggered by the same dose (1 mg/kg) of METH on the reinstatement test day. Meanwhile, NaB (400 mg/kg) per se had no effect on the natural preference of mice, but injections of NaB during the conditioning and extinction phases facilitated the acquisition and extinction of METH-induced CPP, respectively. Additionally, although the effect of a single NaB injection prior to the trigger of CPP reinstatement was not observed, repeated NaB injections during the extinction phase totally blocked the reinstatement of METH-induced CPP. Taken together, our results suggested a specific effect of histone acetylation on modulating distinct phases of METH-induced CPP and that treatment of NaB during the extinction phase not only produced beneficial effects on eliminating already established CPP but also blocked the reinstatement of METH-induced CPP. © 2016 Wiley Periodicals, Inc.

Histone Acetylation Regulation in Sleep Deprivation-Induced Spatial Memory Impairment.

Sleep disorders negatively affect cognition and health. Recent evidence has indicated that chromatin remodeling via histone acetylation regulates cognitive function. This study aimed to investigate the possible roles of histone acetylation in sleep deprivation (SD)-induced cognitive impairment. Results of the Morris water maze test showed that 3days of SD can cause spatial memory impairment in Wistar rats. SD can also decrease histone acetylation levels, increase histone deacetylase 2 (HDAC2) expression, and decrease histone acetyltransferase (CBP) expression. Furthermore, SD can reduce H3 and H4 acetylation levels in the promoters of the brain-derived neurotrophic factor (Bdnf) gene and thus significantly downregulate BDNF expression and impair the activity of key BDNF signaling pathways (pCaMKII, pErk2, and pCREB). However, treatment with the HDAC inhibitor trichostatin A attenuated all the negative effects induced by SD. Therefore, BDNF and its histone acetylation regulation may play important roles in SD-induced spatial memory impairment, whereas HDAC inhibition possibly confers protection against SD-induced impairment in spatial memory and hippocampal functions.

Role of histone acetylation in long-term neurobehavioral effects of neonatal Exposure to sevoflurane in rats

Human studies, and especially laboratory studies, provide evidence that early life exposure to general anesthesia may affect neurocognitive development via largely unknown mechanisms. We explored whether hippocampal histone acetylation had a role in neurodevelopmental effects of sevoflurane administered to neonatal rats. Male Sprague–Dawley rats were exposed to 3% sevoflurane or were subjected to maternal separation only for 2h daily at postnatal days 6, 7, and 8. The histone deacetylase inhibitor, sodium butyrate (250mg/kg, intraperitoneally), or saline was administered starting 2h prior to anesthesia or maternal separation and continued daily until the end of behavioral tests, which were performed between postnatal days 33 and 50. Upon completion of the behavioral tests, the brain tissues were harvested for further analysis. Rats neonatally exposed to sevoflurane exhibited decreased freezing time in the fear conditioning contextual test and increased escape latency, decreased time in target quadrant, and number of platform crossings in the Morris water maze test. The sevoflurane-exposed rats had lower hippocampal density of dendritic spines, reduced levels of the brain-derived neurotrophic factor, c-fos protein, microtubule-associated protein 2, synapsin1, postsynaptic density protein 95, pCREB/CREB, CREB binding protein, and acetylated histones H3 and H4, and increased levels of histone deacetylases 3 and 8. These neurobehavioral abnormalities were normalized in the sevoflurane-exposed rats treated with sodium butyrate. Our findings provide evidence that neonatal exposure to sevoflurane induces neurobehavioral abnormalities and long-lasting alterations in histone acetylation; normalization of histone acetylation may alleviate the neurodevelopmental side effects of the anesthetic.

Blockade of Histone Deacetylation in the Brain Modulates the Expression of Transcription Factors c-FOS and ZENK and Potentiates the Formation of Long-Term Memory in Neonatal Chicks

The aim of the present work was to study the role of histone acetylation in brain cells in the formation of memory in neonatal chicks by investigating the effects of intracerebral administration of the histone deacetylase inhibitor trichostatin A on the formation of memory in “weak” learning by chicks of a passive avoidance task and on the expression of transcription factors c-Fos and ZENK. Administration of trichostatin A before training led to a significant dose-dependent increase in memory on testing at 24 h. In addition, trichostatin A induced c-Fos and ZENK expression in a number of brain structures: the intermediate medial mesopallium and the hippocampus showed increases in the density of cells expressing ZENK and the intermediate arcopallium and dorsocaudal nidopallium showed increases in cells expressing c-Fos. Subsequent learning did not produce additional expression of these genes in any of these structures. These results demonstrate the possibility of increasing “weak” memory in chicks using a histone deacetylase inhibitor, supporting the hypothesis that histone acetylation has a role in the consolidation of long-term memory. This effect may be linked with activation of the expression of transcription factor genes in brain structures involved in memory consolidation in this model.

Histone Acetylation and Its Modifiers in the Pathogenesis of Diabetic Nephropathy.

Diabetic nephropathy (DN) remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors contributing to DN is required to develop more effective therapeutic options. It is becoming more evident that histone acetylation (HAc), as one of the epigenetic mechanisms, is thought to be associated with the etiology of diabetic vascular complications such as diabetic retinopathy (DR), diabetic cardiomyopathy (DCM), and DN. Histone acetylases (HATs) and histone deacetylases (HDACs) are the well-known regulators of reversible acetylation in the amino-terminal domains of histone and nonhistone proteins. In DN, however, the roles of histone acetylation (HAc) and these enzymes are still controversial. Some new evidence has revealed that HATs and HDACs inhibitors are renoprotective in cellular and animal models of DN, while, on the other hand, upregulation of HAc has been implicated in the pathogenesis of DN. In this review, we focus on the recent advances on the roles of HAc and their covalent enzymes in the development and progression of DN in certain cellular processes including fibrosis, inflammation, hypertrophy, and oxidative stress and discuss how targeting these enzymes and their inhibitors can ultimately lead to the therapeutic approaches for treating DN.

Role of Histone Acetylation in Cell Cycle Regulation.

Core histone acetylation is a key prerequisite for chromatin decondensation and plays a pivotal role in regulation of chromatin structure, function and dynamics. The addition of acetyl groups disturbs histone/DNA interactions in the nucleosome and alters histone/histone interactions in the same or adjacent nucleosomes. Acetyl groups can also provide binding sites for recruitment of bromodomain (BRD)-containing non-histone readers and regulatory complexes to chromatin allowing them to perform distinct downstream functions. The presence of a particular acetylation pattern influences appearance of other histone modifications in the immediate vicinity forming the "histone code". Although the roles of the acetylation of particular lysine residues for the ongoing chromatin functions is largely studied, the epigenetic inheritance of histone acetylation is a debated issue. The dynamics of local or global histone acetylation is associated with fundamental cellular processes such as gene transcription, DNA replication, DNA repair or chromatin condensation. Therefore, it is an essential part of the epigenetic cell response to processes related to internal and external signals.

HISTONE DEACETYLASE6-Defective Mutants Show Increased Expression and Acetylation of ENHANCER OF TRIPTYCHON AND CAPRICE1 and GLABRA2 with Small But Significant Effects on Root Epidermis Cellular Pattern.

Cellular patterning in the Arabidopsis (Arabidopsis thaliana) root epidermis is dependent on positional information, the transmission of which involves histone acetylation. Here, we report that HISTONE DEACETYLASE6 (HDA6) has significant effects on this cellular patterning. Mutation of HDA6 led to ectopic hair cells in the nonhair positions of root epidermis in Arabidopsis, based on an analysis of paraffin sections stained with Toluidine Blue. While HDA6 was present throughout the root tip, epidermis-specific complementation with HDA6 could rescue the hda6 phenotype. Both transcript levels and expression patterns of ENHANCER OF TRIPTYCHON AND CAPRICE1 (ETC1) and GLABRA2 (GL2) in the root tip were affected in hda6. Consistent with these changes in expression, HDA6 directly bound to the promoter regions of ETC1 and GL2, and acetylation of histone H3 on these promoter regions and acetylation of histone H4 on the ETC1 promoter region was increased in the hda6 mutant. Taken together, these results indicate that HDA6 affects the cellular patterning of Arabidopsis root epidermis through altering the histone acetylation status of ETC1 and GL2 promoters and thereby affects the expression of these two components of the core transcription factor network determining epidermal cell fates. Our findings thus provide new insights into the role of histone acetylation in root epidermis cell patterning.

The role of histone acetylation in the basolateral amygdala in morphine-associated memory in rats

To examine the regulatory effect of histone acetylation on memory related molecules, 34 healthy male SD rats were randomly divided into control and basolateral amygdala (BLA) intracranial positioning operation groups. In the process of conditioned place preference (CPP) training, Trichostafin A (TSA) was administrated by the route of BLA and morphine was injected into enterocoelia with dimethyl sulfoxide or saline as control. Expression levels of H3K14 acetylation and brain-derived neurotrophic factor (BDNF) in BLA were evaluated by Western blotting.The results showed that CPP could be established by intraperitoneal injection of morphine. Compared with control groups, a stronger place preference was established and expression of H3K14 acetylation and BDNF was significantly increased in the group treated with TSA and morphine. In addition, there was a synergistic effect between morphine and TSA. Our results suggested that the level of histone acetylation in BLA is associated with the formation of morphine memory in rats. Inhibition of the activity of histone deacetylases in BLA can promote the formation of cue-associated memory induced by morphine and the involvement of BDNF in BLA maybe was regulated by histone acetylation.

Defining the orphan functions of lysine acetyltransferases.

Long known for their role in histone acetylation, recent studies have demonstrated that lysine acetyltransferases also carry out distinct “orphan” functions. These activities impact a wide range of biological phenomena including metabolism, RNA modification, nuclear morphology, and mitochondrial function. Here, we review the discovery and characterization of orphan lysine acetyltransferase functions. In addition to highlighting the evidence and biological role for these functions in human disease, we discuss the part emerging chemical tools may play in investigating this versatile enzyme superfamily.

Role of histone acetylation and dopaminergic signalling in promoting long-term and context-independent fear extinction

Role of histone acetylation and dopaminergic signalling in promoting long-term and context-independent fear extinction

From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects.

The superordinate principles governing the transcriptome response of differentiating cells exposed to drugs are still unclear. Often, it is assumed that toxicogenomics data reflect the immediate mode of action (MoA) of drugs. Alternatively, transcriptome changes could describe altered differentiation states as indirect consequence of drug exposure. We used here the developmental toxicants valproate and trichostatin A to address this question. Neurally differentiating human embryonic stem cells were treated for 6 days. Histone acetylation (primary MoA) increased quickly and returned to baseline after 48 h. Histone H3 lysine methylation at the promoter of the neurodevelopmental regulators PAX6 or OTX2 was increasingly altered over time. Methylation changes remained persistent and correlated with neurodevelopmental defects and with effects on PAX6 gene expression, also when the drug was washed out after 3–4 days. We hypothesized that drug exposures altering only acetylation would lead to reversible transcriptome changes (indicating MoA), and challenges that altered methylation would lead to irreversible developmental disturbances. Data from pulse-chase experiments corroborated this assumption. Short drug treatment triggered reversible transcriptome changes; longer exposure disrupted neurodevelopment. The disturbed differentiation was reflected by an altered transcriptome pattern, and the observed changes were similar when the drug was washed out during the last 48 h. We conclude that transcriptome data after prolonged chemical stress of differentiating cells mainly reflect the altered developmental stage of the model system and not the drug MoA. We suggest that brief exposures, followed by immediate analysis, are more suitable for information on immediate drug responses and the toxicity MoA.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-014-1279-6) contains supplementary material, which is available to authorized users.

Contrasting Effects of Histone Deacetylase Inhibitors on Reward and Aversive Olfactory Memories in the Honey Bee.

Much of what we have learnt from rodent models about the essential role of epigenetic processes in brain plasticity has made use of aversive learning, yet the role of histone acetylation in aversive memory in the honey bee, a popular invertebrate model for both memory and epigenetics, was previously unknown. We examined the effects of histone deacetylase (HDAC) inhibition on both aversive and reward olfactory associative learning in a discrimination proboscis extension reflex (PER) assay. We report that treatment with the HDAC inhibitors APHA compound 8 (C8), phenylbutyrate (PB) or sodium butyrate (NaB) impaired discrimination memory due to impairment of aversive memory in a dose-dependent manner, while simultaneously having no effect on reward memory. Treatment with C8 1 h before training, 1 h after training or 1 h before testing, impaired aversive but not reward memory at test. C8 treatment 1 h before training also improved aversive but not reward learning during training. PB treatment only impaired aversive memory at test when administered 1 h after training, suggesting an effect on memory consolidation specifically. Specific impairment of aversive memory (but not reward memory) by HDAC inhibiting compounds was robust, reproducible, occurred following treatment with three drugs targeting the same mechanism, and is likely to be genuinely due to alterations to memory as sucrose sensitivity and locomotion were unaffected by HDAC inhibitor treatment. This pharmacological dissection of memory highlights the involvement of histone acetylation in aversive memory in the honey bee, and expands our knowledge of epigenetic control of neural plasticity in invertebrates.

Trrap-Dependent Histone Acetylation Specifically Regulates Cell-Cycle Gene Transcription to Control Neural Progenitor Fate Decisions

Fate decisions in neural progenitor cells are orchestrated via multiple pathways, and the role of histone acetylation in these decisions has been ascribed to a general function promoting gene activation. Here, we show that the histone acetyltransferase (HAT) cofactor transformation/transcription domain-associated protein (Trrap) specifically regulates activation of cell-cycle genes, thereby integrating discrete cell-intrinsic programs of cell-cycle progression and epigenetic regulation of gene transcription in order to control neurogenesis. Deletion of Trrap impairs recruitment of HATs and transcriptional machinery specifically to E2F cell-cycle target genes, disruptingtheir transcription with consequent cell-cycle lengthening specifically within cortical apical neural progenitors (APs). Consistently, Trrap conditional mutants exhibit microcephaly because of premature differentiation of APs into intermediate basal progenitors and neurons, and overexpressing cell-cycle regulators invivo can rescue these premature differentiation defects. These results demonstrate an essential and highly specific role for Trrap-mediated histone regulation in controlling cell-cycle progression and neurogenesis.

Role of histone acetylation in diabetes mellitus

Histone acetylation is a crucial part histone modifications in epigenetics.Histone acetylation is involved in the onset diabetes and diabetic complications,through the mechanism inducing hyperglycemia by means of metabolic memory effect,interfering islet development and regulating the expression inflammatory factors and pathogenic genes.Genome-wide association studies are gradually unveilling the pathogenesis diabetes and preclinical studies are rapidly elucidating that histone deacetylase should be considered as a new target for the treatment diabetes. Key words: Diabetes mellitus; Histone acetylation; Metabolic memory; Genome wide association studies

Critical Role of Histone Acetylation by p300 in Human Placental 11β-HSD2 Expression

Fetal overexposure to glucocorticoids leads to growth restriction. Optimal fetal glucocorticoid level is ensured by the expression of cortisol-inactivating enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in placental syncytiotrophoblasts. The transcription factor selective promoter factor 1 (Sp1) is known to up-regulate 11β-HSD2 expression in the presence of enhanced histone acetylation in syncytiotrophoblasts, but the mechanisms underlying histone acetylation remain unknown. The role of p300 in histone acetylation associated with 11β-HSD2 expression in syncytiotrophoblasts was investigated. Distribution of p300 in human placenta was studied with immunohistochemistry. The role of p300 in histone-3 (H3) acetylation in association with 11β-HSD2 expression was investigated in cultured primary human placental trophoblasts in the presence of small interfering RNA (siRNA)-mediated knockdown of p300, p300 inhibitor C646, or p300 overexpression. The interaction of Sp1 and p300 was studied with chromatin immunoprecipitation and coimmunoprecipitation. Intense staining of p300 was found in the nuclei of trophoblasts. Levels of p300 and acetyl H3K9 and H3K27 associated with 11β-HSD2 promoter were increased in the course of syncytialization and by cAMP pathway activation. Chromatin immunoprecipitation and coimmunoprecipitation revealed p300 and Sp1 on 11β-HSD2 promoter and in the same protein complex in the syncytiotrophoblasts. Overexpression of p300 enhanced 11β-HSD2 expression, which was attenuated by Sp1 knockdown, whereas p300 knockdown and C646 reduced both basal and cAMP-stimulated acetylation of H3K9 and H3K27 associated with 11β-HSD2 expression. Interaction of p300 with Sp1 plays a crucial role in histone acetylation associated with 11β-HSD2 expression in syncytiotrophoblasts, which may have important implications in the establishment of the placental glucocorticoid barrier in gestation.

Effects of sodium butyrate on methamphetamine-sensitized locomotor activity

Neuroadaptations associated with behavioral sensitization induced by repeated exposure to methamphetamine (MA) appear to be involved in compulsive drug pursuit and use. Increased histone acetylation, an epigenetic effect resulting in altered gene expression, may promote sensitized responses to psychostimulants. The role of histone acetylation in the expression and acquisition of MA-induced locomotor sensitization was examined by measuring the effect of histone deacetylase inhibition by sodium butyrate (NaB). For the effect on expression, mice were treated repeatedly with MA (10 days of 2mg/kg MA) or saline (10 days), and then vehicle or NaB (630mg/kg, intraperitoneally) was administered 30 min prior to MA challenge and locomotor response was measured. NaB treatment increased the locomotor response to MA in both acutely MA treated and sensitized animals. For acquisition, NaB was administered 30min prior to each MA exposure (10 days of 1 or 2mg/kg), but not prior to the MA challenge test. Treatment with NaB during the sensitization acquisition period significantly increased locomotor activation by MA in sensitized mice only. NaB alone did not significantly alter locomotor activity. Acute NaB or MA, but not the combination, increased striatal acetylation at histone H4. Repeated treatment with MA, but not NaB or MA plus NaB, increased striatal acetylation at histone H3. Although increased histone acetylation may alter the expression of genes involved in acute locomotor response to MA and in the acquisition of MA-induced sensitization, results for acetylation at H3 and H4 showed little correspondence with behavior.

Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia: role of histone acetylation

High-altitude long-term hypoxia (LTH) is known to induce pulmonary arterial smooth muscle cell (PASMC) proliferation in the fetus, leading to pulmonary arterial remodeling and pulmonary hypertension of the newborn. The mechanisms underlying these conditions remain enigmatic however. We hypothesized that epigenetic alterations in fetal PASMC induced by high-altitude LTH may play an important role in modulating their proliferation during pulmonary arterial remodeling. To test this hypothesis, we have analyzed epigenetic alterations in the pulmonary vasculature of fetal lambs exposed to high-altitude LTH [pregnant ewes were kept at 3,801 m altitude from ~40 to 145 days gestation] or to sea level atmosphere. Intrapulmonary arteries were isolated, and fetal PASMC were cultured from both control and LTH fetuses. Compared with controls, in LTH fetus pulmonary arteries measurements of histone acetylation and global DNA methylation demonstrated reduced levels of global histone 4 acetylation and DNA methylation, accompanied by the loss of the cyclin-dependent kinase inhibitor p21. Treatment of LTH fetal PASMCs with histone deacetylase (HDAC) inhibitor trichostatin A decreased their proliferation rate, in part because of altered expression of p21 at both RNA and protein level. In PASMC of LTH fetuses, HDAC inhibition also decreased PDGF-induced cell migration and ERK1/2 activation and modulated global DNA methylation. On the basis of these observations, we propose that epigenetic alterations (reduced histone acetylation and DNA methylation) caused by chronic hypoxia leads to fetal PASMC proliferation and vessel remodeling associated with vascular proliferative disease and that this process is regulated by p21.

Sphingosine Kinase 1 Is Required for Mesothelioma Cell Proliferation: Role of Histone Acetylation

BackgroundMalignant pleural mesothelioma (MPM) is a devastating disease with an overall poor prognosis. Despite the recent advances in targeted molecular therapies, there is a clear and urgent need for the identification of novel mesothelioma targets for the development of highly efficacious therapeutics.Methodology/Principal FindingsIn this study, we report that the expression of Sphingosine Kinase 1 (SphK1) protein was preferentially elevated in MPM tumor tissues (49 epithelioid and 13 sarcomatoid) compared to normal tissue (n = 13). In addition, we also observed significantly elevated levels of SphK1 and SphK2 mRNA and SphK1 protein expression in MPM cell lines such as H2691, H513 and H2461 compared to the non-malignant mesothelial Met5 cells. The underlying mechanism appears to be mediated by SphK1 induced upregulation of select gene transcription programs such as that of CBP/p300 and PCAF, two histone acetyl transferases (HAT), and the down regulation of cell cycle dependent kinase inhibitor genes such as p27Kip1 and p21Cip1. In addition, using immunoprecipitates of anti-acetylated histone antibody from SphK inhibitor, SphK-I2 treated Met5A and H2691 cell lysates, we also showed activation of other cell proliferation related genes, such as Top2A (DNA replication), AKB (chromosome remodeling and mitotic spindle formation), and suppression of p21 CIP1 and p27KIP1. The CDK2, HAT1 and MYST2 were, however, unaffected in the above study. Using SphK inhibitor and specific siRNA targeting either SphK1 or SphK2, we also unequivocally established that SphK1, but not SphK2, promotes H2691 mesothelioma cell proliferation. Using a multi-walled carbon nanotubes induced peritoneal mesothelioma mouse model, we showed that the SphK1−/− null mice exhibited significantly less inflammation and granulamatous nodules compared to their wild type counterparts.Conclusions/SignificanceThe lipid kinase SphK1 plays a positive and essential role in the growth and development of malignant mesothelioma and is therefore a likely therapeutic target.

The Role of Histone Acetylation in Cocaine-Induced Neural Plasticity and Behavior

How do drugs of abuse, such as cocaine, cause stable changes in neural plasticity that in turn drive long-term changes in behavior? What kind of mechanism can underlie such stable changes in neural plasticity? One prime candidate mechanism is epigenetic mechanisms of chromatin regulation. Chromatin regulation has been shown to generate short-term and long-term molecular memory within an individual cell. They have also been shown to underlie cell fate decisions (or cellular memory). Now, there is accumulating evidence that in the CNS, these same mechanisms may be pivotal for drug-induced changes in gene expression and ultimately long-term behavioral changes. As these mechanisms are also being found to be fundamental for learning and memory, an exciting new possibility is the extinction of drug-seeking behavior by manipulation of epigenetic mechanisms. In this review, we critically discuss the evidence demonstrating a key role for chromatin regulation via histone acetylation in cocaine action.

Epigenetics of the depressed brain: role of histone acetylation and methylation.

Major depressive disorder is a chronic, remitting syndrome involving widely distributed circuits in the brain. Stable alterations in gene expression that contribute to structural and functional changes in multiple brain regions are implicated in the heterogeneity and pathogenesis of the illness. Epigenetic events that alter chromatin structure to regulate programs of gene expression have been associated with depression-related behavior, antidepressant action, and resistance to depression or 'resilience' in animal models, with increasing evidence for similar mechanisms occurring in postmortem brains of depressed humans. In this review, we discuss recent advances in our understanding of epigenetic contributions to depression, in particular the role of histone acetylation and methylation, which are revealing novel mechanistic insight into the syndrome that may aid in the development of novel targets for depression treatment.