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Atherosclerosis is the leading cause of mortality and morbidity in the developed world. It is characterized by the formation of a plaque in the walls of middle and large arteries leading to macrovascular complications. Several risk factors are included, with diabetes being one of the most important for the onset and development of atherosclerosis. Due to an increase in the prevalence of diabetes in the world, the incidence of diabetic complications (microvascular and macrovascular) is increasing. Peroxisome proliferator-activated receptor γ (PPARγ) plays a important role in atherosclerotic processes. Peroxisome proliferator activated receptor γ belongs to the superfamily of nuclear receptors, has a great presence in fat tissue, macrophages, and regulates gene expression and most of the processes that lead to the onset and development of atherosclerosis. In this review, we discuss the basic patho-physiological mechanisms of atherosclerosis in type 2 diabetes mellitus (T2DM). Furthermore, we discuss the impact of PPARγ polymorphisms, and the epigenetic mechanisms affecting the onset of atherosclerosis, i.e, DNA methylation and demethylation, histone acetylation and deacetylation, and RNA-based mechanisms. Moreover, we add therapeutic possibilities for acting on epigenetic mechanisms in order to prevent the onset and progression of atherosclerosis.

Histone acetylation and deacetylation are important epigenetic mechanisms that regulate gene expression and transcription. Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family that not only participates in histone acetylation and deacetylation but also targets several nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 (HSP90), to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. Furthermore, HDAC6 also upregulates several critical factors in the immune system, such as program death receptor-1 (PD-1) and program death receptor ligand-1 (PD-L1) receptor, which are the main targets for cancer immunotherapy. Several selective HDAC6 inhibitors are currently in clinical trials for cancer treatment and bring hope for patients with malignant tumors. A fuller understanding of HDAC6 as a critical regulator of many cellular pathways will help further the development of targeted anti-HDAC6 therapies. Here, we review the unique features of HDAC6 and its role in cancer, which make HDAC6 an appealing drug target.

Neuroplasticity remodels sensory cortex across the lifespan. A function of adult sensory cortical plasticity may be capturing available information during perception for memory formation. The degree of experience-dependent remodeling in sensory cortex appears to determine memory strength and specificity for important sensory signals. A key open question is how plasticity is engaged to induce different degrees of sensory cortical remodeling. Neural plasticity for long-term memory requires the expression of genes underlying stable changes in neuronal function, structure, connectivity, and, ultimately, behavior. Lasting changes in transcriptional activity may depend on epigenetic mechanisms; some of the best studied in behavioral neuroscience are DNA methylation and histone acetylation and deacetylation, which, respectively, promote and repress gene expression. One purpose of this review is to propose epigenetic regulation of sensory cortical remodeling as a mechanism enabling the transformation of significant information from experiences into content-rich memories of those experiences. Recent evidence suggests how epigenetic mechanisms regulate highly specific reorganization of sensory cortical representations that establish a widespread network for memory. Thus, epigenetic mechanisms could initiate events to establish exceptionally persistent and robust memories at a systems-wide level by engaging sensory cortical plasticity for gatingwhatandhow muchinformation becomes encoded.

Histone lysine acetylation is well known for being important in the epigenetic regulation of gene expression in eukaryotic cells. Recent studies have uncovered a plethora of acetylated proteins involved in important metabolic pathways, such as photosynthesis and respiration in plants. Enzymes involved in histone acetylation and deacetylation are being identified as regulators of acetylation of metabolic enzymes. Importantly, key metabolites, such as acetyl-CoA and NAD(+), are involved in protein acetylation and deacetylation processes, and their cellular levels may regulate the activity of histone acetyltransferases (HAT) and deacetylases (HDAC). Further research is required to determine whether and how HATs and HDACs sense cellular metabolite signals to control gene expression and metabolic enzyme activity through lysine acetylation and deacetylation.

Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129∗]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024∗]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.

Aberrant histone acetylation and deacetylation are increasingly thought to play important roles in the pathogenesis of rheumatoid arthritis (RA). However, limited data from studies about the activity of histone deacetylases (HDACs) and histone acetyltransferase (HAT) in RA are controversial. Those conflicting results may be caused by sample size, medication, and age- and sex-matched controls. The aim of this study is to investigate the expression and activity of class I HDACs (1–3.8) and their effects on histone acetylation in peripheral blood mononuclear cells (PBMCs) from RA patients. The expression of class I HDACs in PBMCs from RA patients was decreased in both mRNA and protein levels in comparison with HCs. The nuclear HAT activities were dramatically increased. Further, we found HDAC3 activity to be the most significantly reduced in overall reduction of HDACs in the RA group. The extent of total histone H3, but not H4, acetylation in PBMCs from RA patients was increased compared to that in healthy controls (HCs) (p<0.01). In RA PBMCs, the activity and expression of class I HDACs are decreased, which is accompanied with enhanced HAT activity. An altered balance between HDAC and HAT activity was found in RA PBMCs.

Although histone acetylation and deacetylation machineries (HATs and HDACs) regulate important aspects of cell function by targeting histone tails, recent work highlights that non-histone protein acetylation is also pervasive in eukaryotes. Here, we use quantitative mass-spectrometry to define acetylations targeted by the sirtuin family, previously implicated in the regulation of non-histone protein acetylation. To identify HATs that promote acetylation of these sites, we also performed this analysis in gcn5 (SAGA) and esa1 (NuA4) mutants. We observed strong sequence specificity for the sirtuins and for each of these HATs. Although the Gcn5 and Esa1 consensus sequences are entirely distinct, the sirtuin consensus overlaps almost entirely with that of Gcn5, suggesting a strong coordination between these two regulatory enzymes. Furthermore, by examining global acetylation in an ada2 mutant, which dissociates Gcn5 from the SAGA complex, we found that a subset of Gcn5 targets did not depend on an intact SAGA complex for targeting. Our work provides a framework for understanding how HAT and HDAC enzymes collaborate to regulate critical cellular processes related to growth and division.

In eukaryotic cells, histone acetylation and deacetylation play an important role in the regulation of gene expression. Histone acetylation levels are modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Recent studies indicate that HDACs play essential roles in the regulation of gene expression in plant response to environmental stress. In this review, we discussed the recent advance regarding the plant HDACs and their functions in the regulation of abiotic stress responses. The role of HDACs in autophagy was also discussed.

Background Histone acetylation and deacetylation are essential for gene regulation and have been implicated in the regulation of plant hormone responses. Many studies have indicated the role of histone acetylation in ethylene signaling; however, few studies have investigated how ethylene signaling regulates the genomic landscape of chromatin states. Recently, we found that ethylene can specifically elevate histone H3K14 acetylation and the non-canonical histone H3K23 acetylation in etiolated seedlings and the gene activation is positively associated with the elevation of H3K14Ac and H3K23Ac in response to ethylene. To assess the role of H3K9, H3K14, and H3K23 histone modifications in the ethylene response, we examined how ethylene regulates histone acetylation and the transcriptome at global level and in ethylene regulated genes both in wild type (Col-0) and ein2-5 seedlings. Results Our results revealed that H3K9Ac, H3K14Ac, and H3K23Ac are preferentially enriched around the transcription start sites and are positively correlated with gene expression levels in Col-0 and ein2-5 seedlings both with and without ethylene treatment. In the absence of ethylene, no combinatorial effect of H3K9Ac, H3K14Ac, and H3K23Ac on gene expression was detected. In the presence of ethylene, however, combined enrichment of the three histone acetylation marks was associated with high gene expression levels, and this ethylene-induced change was EIN2 dependent. In addition, we found that ethylene-regulated genes are expressed at medium or high levels, and a group of ethylene regulated genes are marked by either one of H3K9Ac, H3K14Ac or H3K23Ac. In this group of genes, the levels of H3K9Ac were altered by ethylene, but in the absence of ethylene the levels of H3K9Ac and peak breadths are distinguished in up- and down- regulated genes. In the presence of ethylene, the changes in the peak breadths and levels of H3K14Ac and H3K23Ac are required for the alteration of gene expressions. Conclusions Our study reveals that the plant hormone ethylene induces combinatorial effects of H3K9Ac, K14Ac and K23Ac histone acetylation in gene expression genome widely. Further, for a group of ethylene regulated genes, in the absence of ethylene the levels and the covered breadths of H3K9Ac are the preexist markers for distinguishing up- and down- regulated genes, the change in the peak breadths and levels of H3K14Ac and H3K23Ac are required for the alteration of gene expression in the presence of ethylene. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3929-6) contains supplementary material, which is available to authorized users.

DCs develop from multipotent progenitors (MPPs), which commit into DC-restricted common dendritic cell progenitors (CDPs). CDPs further differentiate into classical DCs (cDCs) and plasmacytoid DCs (pDCs). Here, we studied the impact of histone acetylation on DC development in C57BL/6 mice by interfering with histone acetylation and deacetylation, employing histone deacetylase (HDAC) inhibitors. We observed that commitment of MPPs into CDPs was attenuated by HDAC inhibition and that pDC development was specifically blocked. Gene expression profiling revealed that HDAC inhibition prevents establishment of a DC-specific gene expression repertoire. Importantly, protein levels of the core DC transcription factor PU.1 were reduced in HDAC inhibitor-treated cells and consequently PU.1 recruitment at PU.1 target genes Fms-like tyrosine kinase 3 (Flt3), interferon regulatory factor 8 (IRF8), and PU.1 itself was impaired. Thus, our results demonstrate that attenuation of PU.1 expression by HDAC inhibition causes reduced expression of key DC regulators, which results in attenuation of DC development. We propose that chromatin modifiers, such as HDACs, are required for establishing a DC gene network, where Flt3/STAT3 signaling drives PU.1 and IRF8 expression and DC development. Taken together, our study identifies HDACs as critical regulators of DC lineage commitment and development.

Histone acetylation and deacetylation play an essential role in the epigenetic regulation of gene expression. Histone deacetylases (HDAC) are a group of zinc-binding metalloenzymes that catalyze the removal of acetyl moieties from lysine residues from histone tails. These enzymes are well known for their wide spread biological effects in eukaryotes. In rice blast fungus, Magnaporthe oryzae, MoRPD3 (an ortholog of Saccharomyces cerevisiae Rpd3) was shown to be required for growth and development. Thus in this study, the class I HDAC, MoRpd3 is considered as a potential drug target, and its 3D structure was modelled and validated. Based on the model, a total of 1880 compounds were virtually screened (molecular docking) against MoRpd3 and the activities of the compounds were assessed by docking scores. The in silico screening suggested that [2-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid (&minus, 8.7 kcal/mol) and [4-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid (&minus, 8.5 kcal/mol) are effective in comparison to trichostatin A (&minus, 7.9 kcal/mol), a well-known general HDAC inhibitor. The in vitro studies for inhibition of appressorium formation by [2-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid has resulted in the maximum inhibition at lower concentrations (1 &mu, M), while the trichostatin A exhibited similar levels of inhibition at 1.5 &mu, M. These findings thus suggest that 3D quantitative structure activity relationship studies on [2-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid compound can further guide the design of more potential and specific HDAC inhibitors.

During B-cell differentiation, the gene expression of B-cell differentiation–related transcription factors must be strictly controlled by epigenetic mechanisms including histone acetylation and deacetylation, to complete the differentiation pathway. GCN5, one of the most important histone acetyltransferases, is involved in epigenetic events for transcriptional regulation through alterations in the chromatin structure. In this study, by analyzing the homozygous DT40 mutants GCN5−/−, generated with gene targeting techniques, we found that GCN5 was necessary for transcriptional activation of IRF-4, an essential transcription factor for plasma cell differentiation. GCN5 deficiency caused drastic decreases in both the mRNA and the protein levels of Blimp-1 and IRF-4. The ectopic expression of Blimp-1 and IRF-4 suggests that IRF-4, but not Blimp-1, is the target gene of GCN5 in immature B cells. Moreover, a chromatin immunoprecipitation assay showed that GCN5 bound to the IRF-4 gene around its 5′-flanking region and acetylated H3K9 residues within chromatin surrounding the region in vivo, suggesting that gene expression of IRF-4 is certainly regulated by GCN5. These results reveal that GCN5 is essential for IRF-4 gene expression, followed by transcriptional activation of Blimp-1, and plays a key role in epigenetic regulation of B-cell differentiation.

Background Microbial-associated molecular patterns activate several MAP kinases, which are major regulators of the innate immune response in Arabidopsis thaliana that induce large-scale changes in gene expression. Here, we determine whether microbial-associated molecular pattern-triggered gene expression involves modifications at the chromatin level. Results Histone acetylation and deacetylation are major regulators of microbial-associated molecular pattern-triggered gene expression and implicate the histone deacetylase HD2B in the reprogramming of defence gene expression and innate immunity. The MAP kinase MPK3 directly interacts with and phosphorylates HD2B, thereby regulating the intra-nuclear compartmentalization and function of the histone deacetylase. Conclusions By studying a number of gene loci that undergo microbial-associated molecular pattern-dependent activation or repression, our data reveal a mechanistic model for how protein kinase signaling directly impacts chromatin reprogramming in plant defense. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1261-8) contains supplementary material, which is available to authorized users.

Dysregulated gene expression resulting from abnormal epigenetic alterations including histone acetylation and deacetylation has been demonstrated to play an important role in driving tumor growth and progression. However, the mechanisms by which specific histone deacetylases (HDACs) regulate differentiation in solid tumors remains unclear. Using pediatric rhabdomyosarcoma (RMS) as a paradigm to elucidate the mechanism blocking differentiation in solid tumors, we identified HDAC3 as a major suppressor of myogenic differentiation from a high-efficiency Clustered regularly interspaced short palindromic repeats (CRISPR)-based phenotypic screen of class I and II HDAC genes. Detailed characterization of the HDAC3-knockout phenotype in vitro and in vivo using a tamoxifen-inducible CRISPR targeting strategy demonstrated that HDAC3 deacetylase activity and the formation of a functional complex with nuclear receptor corepressors (NCORs) were critical in restricting differentiation in RMS. The NCOR/HDAC3 complex specifically functions by blocking myoblast determination protein 1 (MYOD1)-mediated activation of myogenic differentiation. Interestingly, there was also a transient up-regulation of growth-promoting genes upon initial HDAC3 targeting, revealing a unique cancer-specific response to the forced transition from a neoplastic state to terminal differentiation. Our study applied modifications of CRISPR/CRISPR-associated endonuclease 9 (Cas9) technology to interrogate the function of essential cancer genes and pathways and has provided insights into cancer cell adaptation in response to altered differentiation status. Because current pan-HDAC inhibitors have shown disappointing results in clinical trials of solid tumors, therapeutic targets specific to HDAC3 function represent a promising option for differentiation therapy in malignant tumors with dysregulated HDAC3 activity.

Background Involvement of mutations in epigenetic mechanism in the development of heterogeneous MDS and its evolution to AML has been understood with at least one mutation and median of 2-3 mutations of the landscapes of driver mutations in ~40 genes described in >90% MDS patients. Exclusivity and cooperating effects of mutations have directed therapeutic implementation with hypomethylating agents and identified a number of first-in-class small molecules as inhibitors of mutational expression. Preclinical and clinical trials have already been initiated for some synthetic and natural products and established proof-of-concept for mitigation of mutagenic effects. Objective The present review article entails the mutational signatures in DNA-methylation and hydroxymethylation, histone acetylation and Deacetylation, polycomb repressor complex (PRC2), and small molecule inhibitors of these mutational expressions. Method Information has been collected from the recently published literature available mainly through Google search in Medline and PubMed database. Special emphasis was paid on the literature available during 2009-2016. Result The up-to-date information accumulated on signature-mutations and their inhibitors has to integrate the function of clonal hematopoiesis of indeterminate potential (CHIP) and mutational complexities for re-defining MDS-genesis. Nevertheless, molecular understanding of MDS heterogeneity and its transformation to AML is expanding at fast pace with expanding knowledge on abundant non-coding RNAs (ncRNAs), which forms the basis of targeted drug-tailoring, and will further develop personalized medicines based on individual genetic blue-prints. Conclusion Mutation-specific targeted epigenetic drugs, which have already sensitized drug-makers and regulators, may promise attestation of 'del5q and lenalidomide'-like specific drugs for every mutational signature independently or in combination with standard therapeutic elements used for MDS-management, and that will add to understand their antagonistic/synergistic effects.

Introduction Epigenetic modifications, such as histone acetylation and deacetylation, are responsible for maintaining chromatin stability. As such, they have been implicated in a wide range of neurodegenerative disorders. Methods Histone acetylation involves the presentation of an acetyl group to lysine residues at the N terminus of histone proteins. Conversely, histone deacetylation involves the detachment of acetyl groups. Transcriptionally active chromatin is linked to acetylated histones, and in mouse neurons, is implicated in proper learning and memory. Discussion Proper functioning of histone deacetylases (HDACs) plays a pivotal role in histone acetylation homeostasis. Results A wide range of brain disorders are associated with improper balances within histone acetylation mechanisms, resulting in transcriptional dysfunction and translational disparities. Treatment modalities with various HDAC inhibitors have emerged as potential new strategies for therapeutic intervention in neurodegenerative disease. HDAC inhibitors enhance synaptic plasticity, learning and memory in neurodegenerative disorders, such as Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD). In this review, we discuss a variety of in vitro cellular models and in vivo mouse models of neurodegenerative diseases and the potential application of HDAC inhibitors to prevent and treat these disorders.

Histone proteins bind to the DNA backbone to package the DNA into chromatin. Normal histone tails are positively charged because of amine groups that are present on their lysine and arginine residues, and bind to the DNA backbone with phosphate groups that were negatively charged. Histone-related proteins (histone acetyltransferases [HATs] and histone deacetylases [HDACs]) can influence the DNA transcription through the balance between the histone acetylation and deacetylation. Histone acetylation induces loose chromatin by HATs that cause the lysine residue to lose the positive charge. This process is related to the promotion of the DNA transcription. By contrast, histone deacetylation induces condensed chromatin by HDACs that play a role in recovering the positive charge, which is associated with the gene repression. To date, it has been known that mutations, overexpression and improper recruitment of HATs and HDACs develop malignant tumors. Mutations in HATs could lead to increase of histone acetylation.1 Histone acetylation may play an important role in the pathogenesis of lymphoma with the up-regulation of the recombination of the T-cell receptor gene segments.2 But histone hypoacetylation is also involved in the development of tumors through mutations, chromosomal translocations, or the increased activity of HDACs.3 Furthermore, the decrease in histone acetylation is also involved in tumor invasion and metastasis.4 HDACs normally function together with cofactors that recruit HDACs to target genes.5 Their activity is associated with the development of several cancers in human, where more than one mechanism is involved. The transcriptional repression of tumor suppressor-genes by the overexpression and improper recruitment of HDACs to their promoter region could be a common phenomenon in the development and progression of tumors.3 For example, chromosomal translocation is associated with the production of fusion proteins that recruit the HDAC repressor complex with a high affinity to a specific promoter. After that, these multi-protein complexes are involved in the development of the hematological malignancy by the repression of genes that regulate normal differentiation and proliferation of hematopoietic cells.6-8 The aberrant recruitment of HDACs to the E-cadherin promoter may also have an important role in the invasion and metastasis of tumor.9,10 HDAC inhibitors are currently intriguing many researchers who are trying to discover better anticancer agents. Suberoylanilide hydroxamic acid (vorinostat) has been approved by the US Food and Drug Administration (US FDA) for its indication in treating cutaneous T-cell lymphoma (CTCL). To date, however, few studies have examined the expressions of HATs and HDACs in association with malignant lymphoma. Given the above background, we studied the expression of HAT1 and class 1 HDACs including HDAC1, HDAC2, and HDAC3 in reactive lymphoid hyperplasia (RLH), diffuse large B-cell lymphomas (DLBCL), peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS) and extranodal NK/T-cell lymphomas, nasal type (NKTCL) to identify the correlation between the histone acetylation/deacetylation and clinical behavior of the tumor.

We performed a genomewide screen for altered sensitivity to antifungal drugs, including clotrimazole and terbinafine, that target ergosterol biosynthesis using a Schizosaccharomyces pombe gene deletion library consisting of 3,004 nonessential haploid deletion mutants. We identified 109 mutants that were hypersensitive and 11 mutants that were resistant to these antifungals. Proteins whose absence rendered cells sensitive to these antifungals were classified into various functional categories, including ergosterol biosynthesis, membrane trafficking, histone acetylation and deacetylation, ubiquitination, signal transduction, ribosome biosynthesis and assembly, regulation of transcription and translation, cell wall organization and biogenesis, mitochondrion function, amino acid metabolism, nucleic acid metabolism, lipid metabolism, meiosis, and other functions. Also, proteins whose absence rendered cells resistant to these antifungals were classified into functional categories including mitochondrion function, ubiquitination, membrane trafficking, cell polarity, chromatin remodeling, and some unknown functions. Furthermore, the 109 sensitive mutants were tested for sensitivity to micafungin, another antifungal drug that inhibits (1,3)-β- d -glucan synthase, and 57 hypersensitive mutants were identified, suggesting that these mutants were defective in cell wall integrity. Altogether, our findings in fission yeast have shed light on molecular pathways associated with the cellular response to ergosterol biosynthesis inhibitors and may provide useful information for developing strategies aimed at sensitizing cells to these drugs.

金沢大学医薬保健研究域医学系, Histone acetylation and deacetylation have been thought to be related to gene expression, and there are many reports indicating that histone deacetylase inhibitors (HDACis) exert antifibrogenic effects in several organs. In injured livers, hepatic stellate cells (HSCs) are activated in response to profibrogenic mediators and produce large amounts of extracellular matrix. In particular, transforming growth factor-β1 (TGF-β1) is considered as a key factor in accelerating hepatic fibrosis because it is released from activated HSCs and further stimulates them. The present study aimed to clarify whether sodium valproate (VPA) has suppressive effects on cultured human HSCs (LI90). We showed that treatment with VPA had no significantly suppressive effect on cell proliferation at a concentration of 1 mM, which corresponded approximately to the serum concentration obtained by the administration of a clinical dose. However, VPA prevented the morphological changes characteristic for activation and inhibited the expression of collagen type 1 α1 (COL1A1) and TGF-β1 in activated LI90 cells at the mRNA and protein levels. Our results support the hypothesis that VPA exerts antifibrogenic activity with little cytotoxicity at 1 mM, and HDACis are expected to be used in clinical practice for the treatment of fibrotic diseases., Embargo Period 6 months

ISSN 1750-1911 Epigenomics (2014) 6(1), 17–19 Regulation of memory acquisition and extinction by TET1 Evaluation of: Kaas GA, Zhong C, Eason DE et al. TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation. Neuron 79, 1086–1093 (2013); Rudenko A, Dawlaty MM, Seo J et al. Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79, 1109–1122 (2013). Accumulating evidence indicates that altered gene expression in response to changes in the environment underlies the plasticity in the brain, including learning and memory. Epigenetic modifications, such as DNA methylation and histone acetylation, have been shown to critically regulate gene transcription, providing a candidate mechanism for synaptic and experience-dependent behavioral plasticity. The dynamic changes of epigenetic modifications (e.g., histone acetylation and deacetylation) play key roles in memory formation and extinction [1]. Generation of methylated cytosine (5mC) in DNA was once considered as a stable modification to silence gene transcription. However, recent studies indicated that DNA methylation may undergo rapid changes in vivo. The teneleven translocation (TET) family enzymes, TET1, TET2 and TET3, catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and thus participate in active DNA demethylation [2,3]. Guo et al. found that in response to neuronal activation, TET1 mediates demethylation of the Fgf1 and the Bdnf promoters in the brain [4]. However, the potential role of TET1 as well as TET1mediated DNA demethylation in memory formation is not clear. Recent work by Kaas et al. revealed that TET1 exerts function in active DNA demethylation, gene transcription and memory formation [5]. They showed that TET1 is expressed in neurons throughout the hippocampus in the brain and stimulation of neuronal activity by KCl or seizure downregulates its transcription in hippocampal neurons. Overexpression of TET1 in the dorsal hippocampus result in a significant decrease in global level of 5mC and an increase of 5hmC, indicating that TET1 effectively promotes DNA demethylation by converting 5mC to 5hmC. In parallel, upregulation of activity-dependent genes involved in neuroplasticity, such as Fos, Arc, Egr1, Homer1 and Ner4a2 was also detected in the hippocampus overexpressing TET1. Moreover, Kaas et al. investigated the behavioral effects of TET1. Overexpression of TET1 in the dorsal hippocampus does not affect locomotion and anxietylike behavior, but significantly impairs long-term conditioned fear memory. Interestingly, the expression of a catalytically inactive mutant of TET1 also affected gene expression and memory formation, raising the question that if TET1 regulates gene expression and memory via both hydroxylase activity-dependent and hydroxylase activity-independent mechanisms. Earlier research by Zhang and colleagues showed that Tet1-knockout mice exhibit impaired hippocampal neurogenesis and hippocampus-dependent spatial memory [6]. Rudenko et al. recently examined another stain of Tet1-knockout mice generated by depleting exon 4 [7]. They found that ablation of TET1 does not change the level of 5mC but leads to a reduction of Highlights from the latest articles in epigenomics

Many severe human pathologies are related to alterations of the fine balance between histone acetylation and deacetylation; because not all such diseases involve hypoacetylation, but also hyperacetylation, compounds able to enhance or repress the activities of histone acetyltransferases (HATs) could be promising therapeutic agents. We evaluated in vitro and in cell the ability of eleven natural polyisoprenylated benzophenone derivatives to modulate the HAT activity of p300/CBP, an enzyme that plays a pivotal role in a variety of cellular processes. Some of the tested compounds bound efficiently to the p300/CBP protein: in particular, guttiferone A, guttiferone E and clusianone inhibit its HAT activity, whereas nemorosone showed a surprising ability to activate the enzyme. The ability of nemorosone to penetrate cell membranes and modulate histone acetylation into the cell together with its high affinity for the p300/CBP enzyme made this compound a suitable lead for the design of optimized anticancer drugs. Besides, the studies performed at a cellular and molecular level on both the inhibitors and the activator provided new insights into the modulation mechanism of p300/CBP by small molecules.

Acetylation and deacetylation of lysine residues on histones, which are catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), are epigenetic modifications that play a very important role in the regulation of gene transcription. Perturbation of the balance between histone acetylation and deacetylation leads to a myriad of diseases, including cancer, AIDS, malaria, neurodegenerative diseases, and diabetes. HATs and HDACs have recently been recognized as key targets for chemoprevention and drug discovery, and numerous natural and synthetic compounds have been screened in order to identify promising regulators of subtle balance between histone acetylation and deacetylation. Here, we present dietary compounds and other natural products that have emerged as potent HAT or HDAC activity modulators, and we discuss their current and future applications as chemopreventive or therapeutic agents.

The therapeutic benefits of fruits, vegetables, tea and wine are mostly attributed to the presence of phenolic compounds. Naturally occurring dietary polyphenols, such as curcumin (diferuloylmethane, an active component of spice turmeric) and resveratrol (phytoalexin, a fiavanoid found in red wine) can modulate signaling pathways mediated via NF-κB and MAP kinase, and up-regulate glutathione biosynthesis genes through activation of Nrf2. Polyphenols also down-regulate the expression of pro-inflammatory mediators, matrix metalloproteinases and adhesion molecules by inhibiting histone acetyltransferase (HAT) activity and activating histone deacetylases (HDACs)/sirtuins. It has been reported that in severe asthma and in chronic obstructive pulmonary disease (COPD) patients, oxidative stress not only activates the NF-κB pathway but also alters the histone acetylation and deacetylation balance via post-translational modifications of HDACs. Corticosteroids have been one the major modes of therapy against various respiratory diseases, such as asthma and COPD. Failure of corticosteroids to ameliorate such disease conditions is due to the reduction of HDAC2 and SIRT1 levels/activities in lungs of asthmatics and COPD patients. Dietary polyphenols, such as curcumin, resveratrol, and catechins have been reported to modulate epigenetic alterations in various experimental models. The anti-inflammatory property of curcumin, resveratrol, and catechins is associated with their ability to induce HDAC activity and thereby restore the efficacy of glucocorticoids or overcome its resistance. Thus, these polyphenolic compounds have therapeutic value as antioxidants, anti-inflammatory therapy and adjuvant therapy with steroids against chronic inflammatory and epigenetically-regulated diseases. In this chapter we present the current knowledge on the mode of action of these polyphenols in the light of HDACs.

Histone deacetylase (HDAC) inhibitors have been described in detail for their anti-proliferative potency. Recently, an anti-inflammatory property was characterized in vitro and in vivo. This dual efficacy of HDAC inhibitors is highly attractive, since chronic inflammations such as ulcerative colitis are associated with an increased risk of developing carcinomas. Additionally, in models of colitis and inflammation-induced tumorigenesis inflammation as well as tumor development was significantly inhibited by HDAC inhibitor treatment. The mechanisms involved reach beyond the simple regulation of histone acetylation and deacetylation. The currently known key target structures and mechanisms mediating this dual effect will be discussed in this review.

The principal nucleus of the bed nucleus of the stria teminalis (BNSTp) is larger and contains more cells in male mice than in females. These sex differences arise from a higher rate of cell death during early postnatal life in females. Perinatal differences in testosterone appear to create this difference because neonatal testosterone treatment reduces cell death in females to the level seen in males. There is a delay of about six days between testosterone exposure and the peak of cell death, indicating that cells somehow ‘remember’ whether or not they have been exposed to high levels of testosterone. This suggests that epigenetic mechanisms control cell fate. We examined whether histone acetylation, which is typically associated with activation of gene expression, plays a role in the sexual differentiation of the BNSTp. We manipulated the balance between histone acetylation and deacetylation by treating animals with the histone deacetylase inhibitor valproic acid (VPA) at the critical time for sexual differentiation. Males, females, and females treated neonatally with testosterone were treated with 50mg/kg VPA or saline on postnatal days 1 and 2. Animals were sacrificed on postnatal day 21 and volume and cell number of the BNSTp was determined. VPA treatment did not influence volume or cell number in control females but significantly reduced both of these parameters in males and testosterone-treated females, thereby eliminating the sex difference. No volume changes were noted in the suprachiasmatic nucleus, suggesting that the VPA effect was specific to the BNSTp. These findings suggest that a disruption in histone deacetylation blocks the masculinizing actions of testosterone in the BNSTp.

Eukaryotes possess a variety of histone-modifying protein complexes. Generally, a histone-modifying protein complex consists of multiple subunits, that is, a catalytic subunit and the associated subunits. In this study, I analyzed 62 and 48 subunits of the histone-modifying protein complexes ofSaccharomyces cerevisiaeandSchizosaccharomyces pombe, respectively. The evolutionary conservation levels of the 110 subunits were measured. The measurements revealed that the conservation levels of the catalytic subunits are significantly higher than those of the associated subunits of the histone acetyltransferase and deacetylase complexes; however, the conservation level of the catalytic subunits is similar to that of the associated subunits of the histone methyltransferase complexes. Thus, in the fungal histone acetylation and deacetylation systems, the catalytic subunits of histone-modifying protein complexes are conserved and the associated subunits are evolutionary lineage-specific. In contrast, in the fungal histone methylation system, both the catalytic and the associated subunits are evolutionary lineage-specific.

Histone acetylation induces chromatin opening by perturbing higher-order chromatin compaction and folding, suggesting that histone acetylation and deacetylation dynamics are central to chromosome condensation or decondensation. The condensation of chromosomes during mitosis is an essential prerequisite for successful chromosome segregation. In this study, we depleted three representative histone acetyltransferases (HATs; p300, CBP, and P/CAF) using shRNAs to explore their role in regulating mitotic progression and chromosome segregation. We showed that HAT depletion severely interfered with the normal timing of mitotic progression, and it reduced condensin subunit levels. The predominant response to HAT depletion, in both human primary and cancer cells, was a mitotic catastrophe following aberrant mitotic arrest. Alternatively, adaptation to HAT depletion, particularly in cancer cells, led to multinucleation and aneuploidy. Interestingly, mitotic catastrophe induced by HAT depletion appeared to be coupled to the signaling process of H2AX phosphorylation and foci formation, independently of DNA double-strand breaks and DNA damage. Taken together, our results provide novel molecular evidence that HAT proteins maintain mitotic chromatin assembly and integrity as a cellular determinant of mitotic cell death.

The expression of NF-kappaB (NF-kappaB)-dependent pro-inflammatory genes in response to oxidative stress is regulated by the acetylation-deacetylation status of histones bound to the DNA. It has been suggested that in severe asthma and in chronic obstructive pulmonary disease (COPD) patients, oxidative stress not only activates the NF-kappaB pathway but also alters the histone acetylation and deacetylation balance via post-translational modification of histone deacetylases (HDACs). Corticosteroids have been one of the major modes of therapy against various chronic respiratory diseases such as asthma and COPD. Failure of corticosteroids to ameliorate such disease conditions has been attributed to their inability to either recruit HDAC2 or to the presence of an oxidatively modified HDAC2 in asthmatics and COPD subjects. Naturally occurring polyphenols such as curcumin and resveratrol have been increasingly considered as safer nutraceuticals. Curcumin is a polyphenol present in the spice turmeric, which can directly scavenge free radicals such as superoxide anion and nitric oxide and modulate important signaling pathways mediated via NF-kappaB and mitogen-activated protein kinase pathways. Polyphenols also down-regulate expression of pro-inflammatory mediators, matrix metalloproteinases, adhesion molecules, and growth factor receptor genes and they up-regulate HDAC2 in the lung. Thus, curcumin may be a potential antioxidant and anti-inflammatory therapeutic agent against chronic inflammatory lung diseases.

Histone acetylation and deacetylation are among the principal mechanisms by which chromatin is regulated during transcription, DNA silencing, and DNA repair. We analyzed patterns of genetic interactions uncovered during comprehensive genome-wide analyses in yeast to probe how histone acetyltransferase (HAT) and histone deacetylase (HDAC) protein complexes interact. The genetic interaction data unveil an underappreciated role of HDACs in maintaining cellular viability, and led us to show that deacetylation of the histone variant Htz1p at Lys 14 is mediated by Hda1p. Studies of the essential nucleosome acetyltransferase of H4 (NuA4) revealed acetylation-dependent protein stabilization of Yng2p, a potential nonhistone substrate of NuA4 and Rpd3C, and led to a new functional organization model for this critical complex. We also found that DNA double-stranded breaks (DSBs) result in local recruitment of the NuA4 complex, followed by an elaborate NuA4 remodeling process concomitant with Rpd3p recruitment and histone deacetylation. These new characterizations of the HDA and NuA4 complexes demonstrate how systematic analyses of genetic interactions may help illuminate the mechanisms of intricate cellular processes.

Reactive oxygen species (ROS) alter nuclear histone acetylation and deacetylation (chromatin remodeling) leading to increased NF-κB-dependent gene expression of proinflammatory mediators. Naturally occurring dietary polyphenols such as curcumin (diferuloylmethane, an active component of spice turmeric) and resveratrol (phytoalexin, a flavanoid found in red wine) can directly scavenge ROS and modulate signaling pathways mediated via NF-κB and MAP kinase pathways, and upregulate glutathione biosynthesis gene via Nrf2 activation. They also downregulate expression of proinflammatory mediators, matrix metalloproteinases, adhesion molecules, and growth factor receptor genes by inhibiting histone acetyltransferase activity and activating histone deacetylase/sirtuins. Thus, these polyphenolic compounds have therapeutic value as antioxidant and anti-inflammatory therapy against chronic inflammatory epigenetically regulated diseases. Reactive oxygen species play a key role in enhancing the inflammation through sustained activation and phosphorylation of MAP kinases and redox-sensitive transcription factors, such as NF-κB and AP-1, in various inflammatory diseases.1 Oxidative stress also alters nuclear histone acetylation and deacetylation (chromatin remodeling) leading to increased gene expression of proinflammatory mediators.2,3 Recent studies from our laboratory show that oxidative stress enhances lung inflammation via expression of proinflammatory mediators through the activation of intrinsic histone acetyltransferase (HAT) activity of coactivator molecules.4–7 Increased histone acetylation was associated with increased activation of IκB kinase-α and interaction of NF-κB with CBP, leading to increased acetylation of RelA/p65 subunit of NF-κB. Oxidative stress also inhibits the activity of histone deacetylase (HDACs) (decreased HDAC2 levels), activates cells for NF-κB transactivation, and enhances inflammatory gene expression, which leads to chronic inflammatory response both in monocytes and epithelial cells in vitro, and in lungs in vivo.5–7 Oxidative stress also plays a role in poor efficacy of corticosteroids in various chronic inflammatory diseases.2,8 Thus, oxidative stress-mediated aberrant chromatin remodeling or histone modifications can lead to heightened …

A balance of histone acetylation and deacetylation governs the regulation of genes that are involved in the dif- ferentiation and stratification of the mammalian epidermis. Class II HDACs (HDAC4, 5, 6, 7, 9, 10) frequently undergo nucleocytoplasmic flux resulting in gene derepression. Of the Class I HDACs (HDAC1, 2, 3, 8), HDAC2 has only been described in a nuclear setting. Here we report that a specific in vivo subpopulation of epidermal keratinocytes undergoing apoptotic-like terminal differentiation demonstrate complete cytoplasmic sequestration of HDAC2, robust Keratin-10 ex- pression, and canonical nuclear fragmentation. Paralleling our in vivo findings, proteosomal degradation of total cellular HDAC2 enhanced Keratin-10 expression in undifferentiated HFK cells. Forced HDAC2 nuclear overexpression and re- tention results in a partial differentiation block as measured by reduced Keratin-10 expression and delayed chromatin fragmentation. We offer a preliminary model whereby cytoplasmic sequestration of the HDAC2 transcriptional corepres- sor contributes, in part, to the process of mammalian epidermal differentiation. (words 150)

Introduction: Histone deacetylase (HDAC) enzymes control the acetylation status of transcription factors that regulate chromatin structure and gene function. The transcriptional regulatory factors that distinguish histone acetylation and deacetylation patterns by pharmacological HDAC inhibition (HDACi) have not yet been studied. Methods: We analysed sequencing datasets derived from human aortic endothelial cells (HAECs) stimulated with the HDAC inhibitors, Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). We integrated gene expression and histone acetylation profiles with the transcription factor binding site (TFBS) database derived from the Encyclopedia of DNA Elements (ENCODE) project. Results: Overall, TFBS signatures observed in SAHA and TSA stimulated cells were analogous. Histone acetylation was observed at transcription factor binding sites of target genes associated with the silencing factors NRSF, EZH2 and SUZ12. Histone deacetylation was a prominent property of HDACi and correlated with changes in the expression of genes regulated by proteins in transcriptional control such as histone acetyltransferase P300 and lysine demethylase JARID1A, as well as the regulatory factors cMYC, YY1 and STAT family proteins. Conclusion: We identified several transcription factors and coregulators implicated in the regulation of histone modification at target genes mediated by pharmacological HDAC inhibition.

Reversible histone acetylation and deacetylation at the N-terminus of histone tails play a crucial role in regulation of gene activity. Hyperacetylation of histones relaxes chromatin structure and is associated with transcriptional activation, whereas hypoacetylation of histones induces chromatin compaction and gene repression. Histone acetylation and deacetylation are catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Emerging evidences revealed that plant HATs and HDACs play essential roles in regulation of gene expression in plant development and plant responses to environmental stresses. Furthermore, HATs and HDACs were shown to interact with various chromatin-remodeling factors and transcription factors involved in transcriptional regulation of multiple developmental processes.

Histone acetylation and deacetylation promote and repress gene transcription, respectively. Recruitment of histone deacetylases (HDAC) to sites of inflammatory gene transcription has been proposed to explain part of the anti-inflammatory activity of steroids. To examine whether this concept extends to other inflammatory conditions, the current authors investigated the role of histone acetylation and the effects of steroids on the ventilation-induced induction of pro-inflammatory genes. Isolated perfused mouse lungs were ventilated for 180 min with low peak inspiratory pressure of 10 cmH(2)O or high peak inspiratory pressure of 22.5 cmH(2)O (overventilation) and treated with the HDAC inhibitor trichostatin A (TSA), the steroid dexamethasone or both. Overventilation increased histone acetylation at H4K12, as well as gene and protein expression of tumour necrosis factor (TNF), macrophage inflammatory protein (MIP)-2alpha and interleukin (IL)-6; these effects were reversed by dexamethasone. In the presence or absence of dexamethasone, TSA enhanced overventilation-induced induction of TNF and MIP-2alpha, but decreased that of IL-6, indicating that the effects of HDAC are gene dependent. Thus, H4K12 acetylation and its regulation by steroids may be relevant for inflammatory gene transcription during overventilation. Histone deacetylases appear to play an important gene-dependent regulatory role in this process, with the caveat that histones are not the only substrates of histone deacetylase isoenzymes.

Histone acetylation regulates many cellular processes, and specific acetylation marks, either singly or in combination, produce distinct outcomes. For example, the acetylation pattern on newly synthesized histones is important for their assembly into nucleosomes by histone chaperones. Additionally, the degree of chromatin compaction and folding may be regulated by acetylation of histone H4 at lysine 16. Histone acetylation also regulates the formation of heterochromatin; deacetylation of H4 lysine 16 is important for spreading of heterochromatin components, whereas acetylation of this site serves as a barrier to this spreading. Finally, histone acetylation is critical for gene transcription, but recent results suggest that deacetylation of certain sites also plays an important role. There are many histone acetyltransferases (HATs) and deacetylases, with differing preferences for the various histone proteins and for specific sites on individual histones. Determining how these enzymes create distinct acetylation patterns and regulate the functional outcome is an important challenge.

Prostate cancer is the most invasive and frequently occurred cancer in men. In the initial stages, it is androgen dependent and the androgen ablation therapy is effective at this stage. In the final stages, it becomes androgen-independent and is unresponsive to androgen ablation therapy. At this stage, induction of apoptosis is considered as a better strategy to control cancer. Histone acetylation and deacetylation are involved in transcriptional activation and transcriptional repression, respectively. Diallyl disulfide (DADS) induced histone hyperacetylation can be correlated with the expression of antiproliferative genes. Induction of apoptosis by DADS has been correlated with histone acetylation. In the present study, DADS, oil soluble organosulfur compound of garlic, has been studied for its effect on histone acetylation and induction of apoptosis in prostate cancer cells in vitro. The induction of apoptosis has been demonstrated by annexin V-FITC binding assay. Extent of apoptosis has been assessed measuring the activity of caspase-3. The results have shown that DADS induced apoptosis in prostate cancer cells in a dose dependent manner. At both 25 and 40 microM concentrations, DADS increased the number of both early and late apoptotic cells. Histone hyperacetylation was also observed in DADS treated cells. It is concluded that DADS, induces apoptosis by influencing histone acetylation in prostate cancer cells.

The elucidation of mechanisms of chromatin remodeling, particular transcriptional activation, and repression by histone acetylation and deacetylation has shed light on the role of histone deacetylases (HDAC) as a new kind of therapeutic target for human cancer treatment. HDACs, in general, act as components of large corepressor complexes that prevent the transcription of several tumor suppression genes. In addition, they appear to be also involved in the deacetylation of nonhistone proteins. This paper reviews the most recent insights into the diverse biological roles of HDACs as well as the evolution of this important protein family.

The balance of histone acetylation and deacetylation is an epigenetic layer with a critical role in the regulation of gene expression. Histone acetylation induced by histone acetyl transferases (HATs) is associated with gene transcription, while histone hypoacetylation induced by histone deacetylase (HDAC) activity is associated with gene silencing. Altered expression and mutations of genes that encode HDACs have been linked to tumor development since they both induce the aberrant transcription of key genes regulating important cellular functions such as cell proliferation, cell-cycle regulation and apoptosis. Thus, HDACs are among the most promising therapeutic targets for cancer treatment, and they have inspired researchers to study and develop HDAC inhibitors.

The growing appreciation that epigenetic processes are integral to the responses of many organisms to changes in the environment suggests a possible role for epigenetics in coordination of insect diapause. The results we present suggest that histone modification may be one type of epigenetic process that contributes to regulation of pupal diapause in the flesh fly, Sarcophaga bullata. Reduction in total histone H3 acetylation in diapausing pupae, shifts in mRNA expression profiles of genes encoding histone acetyltransferase (HAT) and histone deacetylase (HDAC) in pre-diapause, diapause and post-diapause flies compared to their nondiapause counterparts, and alterations in HDAC enzyme activity during and post-diapause lend support to the hypothesis that this specific type of histone modification is involved in regulating diapause programming, maintenance, and termination. Transcription of genes encoding HDAC1, HDAC3, HDAC6, and Sirtuin2 were all upregulated in photosensitive first instar larvae programmed to enter pupal diapause, suggesting that histone deacetylation may be linked to the early decision to enter diapause. A 50% reduction in transcription of hdac3 and a corresponding 30% reduction in HDAC activity during diapause suggest that removal of acetyl groups from histones primarily occurs prior to diapause entry and that further histone deacetylation is not necessary to maintain diapause. Transcription of the HDAC genes was quickly elevated when diapause was terminated, followed by an increase in enzyme activity after a short delay. A maternal effect operating in these flies prevents pupal diapause in progeny whose mothers experienced pupal diapause, even if the progeny are reared in strong diapause-inducing short-day conditions. Such nondiapausing pupae had HDAC transcription profiles nearly identical to the profiles seen in nondiapausing pupae generated under a long-day photoperiod. Together, these results provide consistent evidence for histone acetylation and deacetylation as regulators of this insect's developmental trajectory.

Candida albicans is the most common opportunistic fungal pathogen, which switches its morphology from single-cell yeast to filament through the various signaling pathways responding to diverse environmental cues. Various transcriptional factors such as Nrg1, Efg1, Brg1, Ssn6, and Tup1 are the key components of these signaling pathways. Since C. albicans can regulate its transcriptional gene expressions using common eukaryotic regulatory systems, its morphological transition by these signaling pathways could be linked to the epigenetic regulation by chromatin structure modifiers. Histone proteins, which are critical components of eukaryotic chromatin structure, can regulate the eukaryotic chromatin structure through their own modifications such as acetylation, methylation, phosphorylation and ubiquitylation. Recent studies revealed that various histone modifications, especially histone acetylation and deacetylation, participate in morphological transition of C. albicans collaborating with well-known transcription factors in the signaling pathways. Here, we review recent studies about chromatin-mediated morphological transition of C. albicans focusing on the interaction between transcription factors in the signaling pathways and histone deacetylases.

Histone acetyltransferase p300/CBP-associated factor (PCAF) belonging to GCN5 family regulates various epigenetic events for transcriptional regulation through alterations in the chromatin structure. During normal development of B cells, gene expressions of numerous transcription factors are strictly regulated by epigenetic mechanisms including histone acetylation and deacetylation to complete their development pathways. Here, by analyzing PCAF-deficient DT40 mutants, ΔPCAF, we report that PCAF takes part in transcriptional activation of B cell lymphoma-6 (Bcl-6) and Paired box gene 5 (Pax5), which are essential transcription factors for normal development of B cells. PCAF-deficiency caused drastic decrease in mRNA levels of Bcl-6 and Pax5, and remarkable increase in that of B lymphocyte-induced maturation protein-1 (Blimp-1). In addition, chromatin immunoprecipitation assay showed that PCAF-deficiency caused remarkable decrease in acetylation levels of both H3K9 and H3K14 residues within chromatin surrounding the 5'-flanking regions of Bcl-6 and Pax5 genes in vivo, suggesting that their gene expressions may be regulated by PCAF. These results revealed that PCAF is involved in transactivation of Bcl-6 and Pax5 genes, resulting in down-regulation of Blimp-1 gene expression, and plays a key role in epigenetic regulation of B cell development.

This Podcast features an interview with Todd Rosen and Bingbing Wang, authors of a Research Article that appears in the 25 August 2015 issue of Science Signaling , about epigenetic changes in the placenta that are induced by glucocorticoids and associated with labor. Hormones control all stages of female reproduction, including the length of gestation and the timing of labor. Corticotropin-releasing hormone (CRH) is produced by the hypothalamus in response to stress, but it is also produced by the placenta during pregnancy. Near the end of gestation, the fetus produces the glucocorticoid cortisol, which stimulates the placenta to increase CRH production. Di Stefano et al . found that glucocorticoids stimulated the expression of CRH in placental cells by promoting dynamic histone acetylation and deacetylation at the CRH promoter through a mechanism that was dependent on the transcription factor NF-κB. These findings identify an epigenetic switch that controls the duration of gestation and the timing of labor and suggest a mechanism by which placental stress induces labor. Listen to Podcast

Nasopharyngeal carcinoma (NPC) is a cancer of the nasopharyngeal epithelium with distinct geographical, ethnic and racial distribution. Several genetic, ethnic and environmental risk factors, have been implicated in nasopharyngeal pathogenesis and of significance, is the Epstein - Barr virus (EBV)- latent infection observed in most patients. Patients with NPC are typically diagnosed only in advanced stages due to non-specific symptoms, and hence, they respond poorly to therapy. Currently, low survival rates, severe complications, tumour metastasis and recurrence following chemo-radiotherapy, delineate the need for better therapeutic options to combat the disease. Recent studies have shown that epigenetic mechanisms such as DNA methylation, histone modifications and microRNAs, which are altered in the EBV genome as well as in the host cells, may underlie the initiation and progression of NPC. Histone acetylation and deacetylation which are mediated by enzymes, namely histone acetyl transferases (HATs) and histone deacetylases (HDACs), are known to regulate gene expression and several cellular processes. HDACs are also involved in maintaining the EBV latent cycle and thus, HDAC inhibitors (HDACi) are potent inducers of EBV reactivation, which is critical for the expression of the lytic proteins, thereby providing novel targets for therapy, as well as mediating enhanced killing of cancer cells, when used alone or along with additional anti-cancer agents in EBV associated malignancies. Recently, three FDA- approved HDACi have been used for the treatment of T-cell lymphoma, while several others are in clinical trials, making histone modifications excellent candidates for targeted therapy. In this review, we summarize the epigenetic mechanisms altered in NPC, with a focus on histone modifications for targeted therapy.

Objective Histone acetylation and deacetylation may play a role in the pathogenesis of inflammatory lung diseases. We evaluated the preventive effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, on neonatal hyperoxic lung injury. Methods Forty newborn rat pups were randomized in normoxia, normoxia+VPA, hyperoxia and hyperoxia+VPA groups. Pups in the normoxia and normoxia+VPA groups were kept in room air and received daily saline and VPA (30 mg/kg) injections, respectively, while those in hyperoxia and hyperoxia+VPA groups were exposed to 95% O2 and received daily saline and VPA (30 mg/kg) injections for 10 days, respectively. Growth, histopathological, biochemical and molecular biological indicators of lung injury, apoptosis, inflammation, fibrosis and histone acetylation were evaluated. Results VPA treatment during hyperoxia significantly improved weight gain, histopathologic grade, radial alveolar count and lamellar body membrane protein expression, while it decreased number of TUNEL(+) cells and active Caspase- 3 expression. Expressions of TGF beta 3 and phospho- SMAD2 proteins and levels of tissue proinflammatory cytokines as well as lipid peroxidation biomarkers were reduced, while anti- oxidative enzyme activities were enhanced by VPA treatment. VPA administration also reduced HDAC activity while increasing acetylated H3 and H4 protein expressions. Conclusions The present study shows for the first time that VPA treatment ameliorates lung damage in a neonatal rat model of hyperoxic lung injury. The preventive effect of VPA involves HDAC inhibition.

Summary Histone acetylation and deacetylation play fundamental roles in transcriptional regulation. We investigated the role of histone deacetylases (HDACs) in human adult haematopoiesis, using the structurally distinct HDAC inhibitors FK228 (depsipeptide) and Trichostatin A. When CD34 + cells were cultured with interleukin (IL)-3 or stem cell factor (SCF) + IL-3, FK228 (0AE5 ng/ml) specifically enhanced the generation of immature erythroid cells with a CD36 + glycophorin A (GPA) low phenotype. In semisolid cultures, FK228 promoted the formation of erythroid colonies by CD34 + cells with IL-3 and SCF + IL-3. Furthermore, upon exposure to FK228, CD34 + cell-derived CD36 + GPA ) cells were induced to form erythroid colonies with IL-3 alone. Conversely, FK228 inhibited the generation of CD36 + GPA high relatively mature erythroid cells from CD34 + cells in the presence of erythropoietin (EPO) and SCF + EPO. FK228 suppressed the EPO-mediated survival of CD36 + GPA low/- and CD36 + GPA high cells and induced their apoptosis. Similar effects were observed for trichostatin A in the generation of erythroid cells in IL-3- and EPO-containing cultures. These data suggest that HDACs negatively regulate the IL-3-mediated growth of early erythroid precursors by suppressing their responsiveness to IL-3, while playing an important role in EPO-mediated differentiation and survival of erythroid precursors. Our data revealed that HDACs have diverse functions in human adult erythropoiesis.

Histone acetylation and deacetylation participate in the epigenetic regulation of gene expression. In this paper, we demonstrate that pre-treatment with the histone deacetylation inhibitor trichostatin A (TSA) enhances histone acetylation in primary cortical neurons and protects against oxygen/glucose deprivation, a model for ischaemic cell death in vitro. The actin-binding protein gelsolin was identified as a mediator of neuroprotection by TSA. TSA enhanced histone acetylation of the gelsolin promoter region, and up-regulated gelsolin messenger RNA and protein expression in a dose- and time-dependent manner. Double-label confocal immunocytochemistry visualized the up-regulation of gelsolin and histone acetylation within the same neuron. Together with gelsolin up-regulation, TSA pre-treatment decreased levels of filamentous actin. The neuroprotective effect of TSA was completely abolished in neurons lacking gelsolin gene expression. In conclusion, we demonstrate that the enhancement of gelsolin gene expression correlates with neuroprotection induced by the inhibition of histone deacetylation.

Histone acetylation and deacetylation are associated with transcriptional activity and the formation of constitutively silent heterochromatin. Increasingly, histone acetylation is also implicated in other chromosome transactions, including replication and segregation. We have cloned the only Schizosaccharomyces pombe MYST family histone acetyltransferase genes, mst1(+) and mst2(+). Mst1p, but not Mst2p, is essential for viability. Both proteins are localized to the nucleus and bound to chromatin throughout the cell cycle. Deltamst2 genetically interacts with mutants that affect heterochromatin, cohesion, and telomere structure. Mst2p is a negative regulator of silencing at the telomere but does not affect silencing in the centromere or mating type region. We generated a census of proteins and histone modifications at wild-type telomeres. A histone acetylation gradient at the telomeres is lost in Deltamst2 cells without affecting the distribution of Taz1p, Swi6p, Rad21p, or Sir2p. We propose that the increased telomeric silencing is caused by histone hypoacetylation and/or an increase in the ratio of methylated to acetylated histones. Although telomere length is normal, meiosis is aberrant in Deltamst2 diploid homozygote mutants, suggesting that telomeric histone acetylation contributes to normal meiotic progression.

A chimeric protein, EWS-Fli1, identified in most Ewing's family tumors (EFTs) has been shown to be associated with the tumorigenicity of EFTs. We have previously reported that p21(Waf1/Cip1) expression was inhibited by EWS-Fli1 in EFTs. Histone deacetylase inhibitors (HDACIs) are known to up-regulate p21(Waf1/Cip1) expression in various cells and show promise as a cancer therapy. Here, we demonstrate the possible involvement of EWS-Fli1 in the activities of both histone acetylation and deacetylation, as well as the potential use of HDACIs as an antitumor agent for EFTs. A novel HDACI, FK228, strongly induced p21(Waf1/Cip1) expression, leading to the hypophosphorylation of retinoblastoma protein (Rb) in EFT cells. Results indicated that EWS-Fli1 deregulated histone acetylation through both the repression of histone acetyltransferase (HAT) and the enhancement of histone deacetylase (HDAC) activities in EFT cells. FK228 treatment blocked both of the abnormal functions of EWS-Fli1. Expressions of EWS-Fli1 protein and mRNA were also inhibited by HDACIs. We suggest that HDACIs might inhibit the expression of EWS-Fli1 via the suppression of the EWS promoter activity. FK228 demonstrated potent growth inhibitory effects on EFT cells at nanomolar concentrations, as well as an apparent distinction in the apoptotic effects between EFT and normal cells. Moreover, intraperitoneal administration of FK228 significantly inhibited tumor growth and induced apoptosis in EFTs in vivo. These results suggest that HDACI might be a promising reagent for use in molecular-based chemotherapy against EFTs.