Chromatin Histone Acetylation Research Articles

PI3K/AKT/mTOR inhibitors as potential extracellular matrix modulators for targeting EMT subtype gastric tumors.

Targeting the extracellular matrix (ECM) is considered as a promising strategy in cancer therapeutics. This study was designed to identify the potential ECM modulators for gastric cancer therapeutics. Exploration of the expression profiles of gastric tumors revealed the elevated expression of ECM genes in gastric tumor tissues compared to the adjacent normal tissues with increased expression in diffuse subtype gastric tumors and specifically in epithelial to mesenchymal transition (EMT) molecular subtype tumors. Consensus ECM gene set was derived from the expression profiles of gastric tumors. The correlative analysis was performed between the expression pattern of the ECM gene set and the drug sensitivity pattern of a panel of drugs across gastric cancer cell lines. Negative correlation between the expression of ECM genes and sensitivity of a number of drugs targeting PI3K/mTOR signaling, chromatin histone acetylation and ABL signaling was observed. These pathways are known for their role in cell-mediated adhesion, differentiation and epithelial to mesenchymal transition. The current results reveal the possibility of using PI3K/AKT/mTOR modulators for targeted gastric cancer therapy in patients with dysregulated ECM.

Repurposing of triamterene as a histone deacetylase inhibitor to overcome cisplatin resistance in lung cancer treatment.

Cisplatin is the core chemotherapeutic drug used for first-line treatment of advanced non-small cell lung cancer (NSCLC). However, drug resistance is severely hindering its clinical efficacy. This study investigated the circumvention of cisplatin resistance by repurposing non-oncology drugs with putative histone deacetylase (HDAC) inhibitory effect. A few clinically approved drugs were identified by a computational drug repurposing tool called "DRUGSURV" and evaluated for HDAC inhibition. Triamterene, originally indicated as a diuretic, was chosen for further investigation in pairs of parental and cisplatin-resistant NSCLC cell lines. Sulforhodamine B assay was used to evaluate cell proliferation. Western blot analysis was performed to examine histone acetylation. Flow cytometry was used to examine apoptosis and cell cycle effects. Chromatin immunoprecipitation was conducted to investigate the interaction of transcription factors to the promoter of genes regulating cisplatin uptake and cell cycle progression. The circumvention of cisplatin resistance by triamterene was further verified in a patient-derived tumor xenograft (PDX) from a cisplatin-refractory NSCLC patient. Triamterene was found to inhibit HDACs. It was shown to enhance cellular cisplatin accumulation and potentiate cisplatin-induced cell cycle arrest, DNA damage, and apoptosis. Mechanistically, triamterene was found to induce histone acetylation in chromatin, thereby reducing the association of HDAC1 but promoting the interaction of Sp1 with the gene promoter of hCTR1 and p21. Triamterene was further shown to potentiate the anti-cancer effect of cisplatin in cisplatin-resistant PDX in vivo. The findings advocate further clinical evaluation of the repurposing use of triamterene to overcome cisplatin resistance.

The APC/CTAD1-WIDE LEAF 1-NARROW LEAF 1 pathway controls leaf width in rice.

Leaf morphology is one of the most important features of the ideal plant architecture. However, the genetic and molecular mechanisms controlling this feature in crops remain largely unknown. Here, we characterized the rice (Oryza sativa) wide leaf 1 (wl1) mutant, which has wider leaves than the wild-type due to more vascular bundles and greater distance between small vascular bundles. WL1 encodes a Cys-2/His-2-type zinc finger protein that interacts with Tillering and Dwarf 1 (TAD1), a co-activator of the anaphase-promoting complex/cyclosome (APC/C) (a multi-subunit E3 ligase). The APC/CTAD1 complex degrades WL1 via the ubiquitin-26S proteasome degradation pathway. Loss-of-function of TAD1 resulted in plants with narrow leaves due to reduced vascular bundle numbers and distance between the small vascular bundles. Interestingly, we found that WL1 negatively regulated the expression of a narrow leaf gene, NARROW LEAF 1 (NAL1), by recruiting the co-repressor TOPLESS-RELATED PROTEIN and directly binding to the NAL1 regulatory region to inhibit its expression by reducing the chromatin histone acetylation. Furthermore, biochemical and genetic analyses revealed that TAD1, WL1, and NAL1 operated in a common pathway to control the leaf width. Our study establishes an important framework for understanding the APC/CTAD1-WL1-NAL1 pathway-mediated control of leaf width in rice, and provides insights for improving crop plant architecture.

KISS1R and ANKRD31 Cooperate to Enhance Leydig Cell Gene Expression via the Cytoskeletal-Nucleoskeletal Pathway.

Kisspeptins are involved in the regulation of hypothalamic-pituitary-gonadal axis, Leydig cell functions, and testosterone secretion, acting as endogenous ligands of the KISS1 receptor. ANKRD31 protein participates in male fertility, regulating meiotic progression, and epididymal sperm maturation. Here, we show that in Leydig cells, KISS1 receptor and ANKRD31 proteins physically interact; the formation of this protein complex is enhanced by Kisspeptin-10 that also modulates F-actin synthesis, favoring histone acetylation in chromatin and gene expression via the cytoskeletal–nucleoskeletal pathway. Kp/KISS1R system deregulation, expression impairment of cytoskeletal–nucleoskeletal mediators, Leydig gene targets, and the decreased testosterone secretion in Ankrd31 −/− testis strongly supported our hypothesis. Furthermore, cytochalasin D treatment subverted the gene expression induction dependent on Kisspeptin-10 action. In conclusion, the current work highlights a novel role for the Kisspeptin-10 in the induction of the cytoskeletal–nucleoskeletal route, downstream a physical interaction between KISS1 receptor and ANKRD31, with gene expression activation as final effect, in Leydig cells.

H3K27ac chromatin acetylation and gene expression analysis reveal sex- and situs-related differences in developing chicken gonads

BackgroundBirds exhibit a unique asymmetry in terms of gonad development. The female left gonad generates a functional ovary, whereas the right gonad regresses. In males, both left and right gonads would develop into testes. How is this left/right asymmetry established only in females but not in males remains unknown. The epigenetic regulation of gonadal developmental genes may contribute to this sex disparity. The modification of histone tails such as H3K27ac is tightly coupled to chromatin activation and gene expression. To explore whether H3K27ac marked chromatin activation is involved in the asymmetric development of avian gonads, we probed genome-wide H3K27ac occupancy in left and right gonads from both sexes and related chromatin activity profile to the expression of gonadal genes. Furthermore, we validated the effect of chromatin activity on asymmetric gonadal development by manipulating the chromatin histone acetylation levels.MethodsThe undifferentiated gonads from both sides of each sex were collected and subjected to RNA-Seq and H3K27ac ChIP-Seq experiments. Integrated analysis of gene expression and active chromatin regions were performed to identify the sex- and situs-specific regulation and expression of gonadal genes. The histone deacetylase inhibitor trichostatin A (TSA) was applied to the undifferentiated female right gonads to assess the effect of chromatin activation on gonadal gene expression and cell proliferation.ResultsEven before sex differentiation, the gonads already show divergent gene expression between different sexes and between left/right sides in females. The sex-specific H3K27ac chromatin distributions coincide with the higher expression of male/female specification genes in each sex. Unexpectedly, the H3K27ac marked chromatin activation show a dramatic difference between left and right gonads in both sexes, although the left/right asymmetric gonadal development was observed only in females but not in males. In females, the side-specific H3K27ac occupancy instructs the differential expression of developmental genes between the pair of gonads and contributes to the development of left but not right gonad. However, in males, the left/right discrepancy of H3K27ac chromatin distribution does not drive the side-biased gene expression or gonad development. The TSA-induced retention of chromatin acetylation causes up-regulation of ovarian developmental genes and increases cell proliferation in the female right gonad.ConclusionsWe revealed that left/right asymmetry in H3K27ac marked chromatin activation exists in both sexes, but this discrepancy gives rise to asymmetric gonadal development only in females. Other mechanisms overriding the chromatin activation would control the symmetric development of male gonads in chicken.

A Ferroptosis-Related lncRNAs Signature Predicts Prognosis and Therapeutic Response of Gastric Cancer.

Background: Accumulating literature demonstrates that long noncoding RNAs (lncRNAs) are involved in ferroptosis and gastric cancer progression. However, the predictive value of ferroptosis-related lncRNAs for prognosis and therapeutic response is yet to be elucidated in gastric cancer (GC). Method: The transcriptomic data and corresponding clinical information of GC patients were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. The association between ferroptosis-related lncRNAs and ferroptosis regulators was analyzed by Spearman correlation analysis. Then, we established a risk predictive model based on the ferroptosis-related lncRNAs using multivariate Cox regression analysis. Furthermore, we performed correlation analysis for the risk score and characteristics of biological processes, immune landscape, stromal activity, genomic integrity, drug response, and immunotherapy efficacy. Results: We constructed a 17-ferroptosis-related-lncRNA signature via multivariate Cox analysis to divide patients into two groups: low- and high-risk groups. The low-risk group was linked to prolonged overall survival and relapse-free survival. The risk score had good predictive ability to predict the prognosis of GC patients compared with other clinical biomarkers. We found that the high-risk group was associated with activation of carcinogenetic signaling pathways, including stromal activation, epithelial-mesenchymal-transition (EMT) activation, and immune escape through integrated bioinformatics analysis. In contrast, the low-risk group was associated with DNA replication, immune-flamed state, and genomic instability. Additionally, through Spearman correlation analysis, we found that patients in the high-risk group may respond well to drugs targeting cytoskeleton, WNT signaling, and PI3K/mTOR signaling, and drugs targeting chromatin histone acetylation, cell cycle, and apoptosis regulation could bring more benefits for the low-risk group. The high-risk group was associated with poor immunotherapy efficacy. Conclusion: Our study systematically evaluated the role of ferroptosis-related lncRNAs in t tumor microenvironment, therapeutic response, and prognosis of GC. Risk score–based stratification could reflect the characteristic of biological processes, immune landscape, stromal activity, genomic stability, and pharmaceutical profile in GC patients. The ferroptosis-related lncRNA signature could serve as a reliable biomarker to predict prognosis and therapeutic response of patients with GC.

Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells.

To evaluate the potential use of Cephaeline as a therapeutic strategy to manage mucoepidermoid carcinomas (MEC) of the salivary glands. UM-HMC-1, UM-HMC-2, and UM-HMC-3A MEC cell lines were used to establish the effects of Cephaeline over tumor viability determined by MTT assay. In vitro wound healing scratch assays were performed to address cellular migration while immunofluorescence staining for histone H3 lysine 9 (H3k9ac) was used to identify the acetylation status of tumor cells upon Cephaeline administration. The presence of cancer stem cells was evaluated by the identification of ALDH enzymatic activity by flow cytometry and through functional assays using in vitro tumorsphere formation. A single administration of Cephaeline resulted in reduced viability of MEC cells along with the halt on tumor growth and cellular migration potential. Administration of Cephaeline resulted in chromatin histone acetylation as judged by the increased levels of H3K9ac and disruption of tumorspheres formation. Interestingly, ALDH levels were increased in UM-HMC-1 and UM-HMC-3A cell lines, while UM-HMC-2 showed a reduced enzymatic activity. Cephaeline has shown anti-cancer properties in all MEC cell lines tested by regulating tumor cells' viability, migration, proliferation, and disrupting the ability of cancer cells to generate tumorspheres.

Histone Deacetylation Inhibitors as Modulators of Regulatory T Cells.

Regulatory T cells (Tregs) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4+Forkhead box protein3+ (CD4+FOXP3+), these cells are a subset of CD4+ T lymphocytes and can originate from the thymus (tTregs) or from the periphery (pTregs). The malfunction of CD4+ Tregs is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional Tregs is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking Treg differentiation might be favorable in sepsis patients. It has been shown that Tregs can be generated from conventional naïve T cells, called iTregs, due to their induced differentiation. Moreover, Tregs can be effectively expanded in vitro based on blood-derived tTregs. Taking into consideration that the suppressive role of Tregs has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of Tregs in this review in detail.

Comprehensive characterization of circular RNAs in ~\u20091000 human cancer cell lines

BackgroundHuman cancer cell lines are fundamental models for cancer research and therapeutic strategy development. However, there is no characterization of circular RNAs (circRNAs) in a large number of cancer cell lines.MethodsHere, we apply four circRNA identification algorithms to heuristically characterize the expression landscape of circRNAs across ~ 1000 human cancer cell lines from CCLE polyA-enriched RNA-seq data. By using integrative analysis and experimental approaches, we explore the expression landscape, biogenesis, functional consequences, and drug response of circRNAs across different cancer lineages.ResultsWe revealed highly lineage-specific expression patterns of circRNAs, suggesting that circRNAs may be powerful diagnostic and/or prognostic markers in cancer treatment. We also identified key genes involved in circRNA biogenesis and confirmed that TGF-β signaling may promote biogenesis of circRNAs. Strikingly, we showed that clinically actionable genes are more likely to generate circRNAs, potentially due to the enrichment of RNA-binding protein (RBP) binding sites. Among these, circMYC can promote cell proliferation. We observed strong association between the expression of circRNAs and the response to drugs, especially those targeting chromatin histone acetylation. Finally, we developed a user-friendly data portal, CircRNAs in cancer cell lines (CircRiC, https://hanlab.uth.edu/cRic), to benefit the biomedical research community.ConclusionsOur study provides the characterization of circRNAs in cancer cell lines and explored the potential mechanism of circRNA biogenesis as well as its therapeutic implications. We also provide a data portal to facilitate the related biomedical researches.

Role of Histone Deacetylases (HDACs) in Epilepsy and Epileptogenesis.

Emerging evidence suggests that epigenetic mechanisms are involved in different brain functions such as the development of the nervous system and normal neuronal function. At the same time, it has been proposed that several neurological diseases are in part, caused by aberrant epigenetic modifications. Nevertheless, the mechanisms underlying pathological alterations in the brain genome are not completely understood. Post-transcriptional histone acetylation is a major mechanism of chromatin remodeling, contributing to epigenetic regulation of gene transcription. Histone deacetylases (HDACs) are a family of proteins involved in both physiological and pathological conditions by regulating the status of chromatin histone acetylation. It is now becoming clear that epigenetic regulatory mechanisms may also play a major role in epilepsy; modulation of chromatin structure through histone modifications has emerged as an important regulator of gene transcription in the brain and altered histone acetylation seems to contribute to changes in gene expression associated with epilepsy and the epileptogenic process. Histone modification is crucial for regulating neurobiological processes such as neural network function, synaptic plasticity, and synaptogenesis which also contribute to the pathophysiology of epilepsy. The role of epigenetics in epilepsy development is a new and emerging research area; the present article reviews the recent findings on the role played by HDACs and the possible function of different histone modifications in epilepsy and epileptogenesis. Inhibitors of HDACs (HDACIs) have been tested in different experimental models of epilepsy with some success. We also review the results from these studies, which indicate HDACIs as potential new therapeutic agents for the treatment of human epilepsy.

N-acetylglucosamine sensing by a GCN5-related N-acetyltransferase induces transcription via chromatin histone acetylation in fungi.

N-acetylglucosamine (GlcNAc) exists ubiquitously as a component of the surface on a wide range of cells, from bacteria to humans. Many fungi are able to utilize environmental GlcNAc to support growth and induce cellular development, a property important for their survival in various host niches. However, how the GlcNAc signal is sensed and subsequently transduced is largely unknown. Here, we identify a gene that is essential for GlcNAc signalling (NGS1) in Candida albicans, a commensal and pathogenic yeast of humans. Ngs1 can bind GlcNAc through the N-terminal β-N-acetylglucosaminidase homology domain. This binding activates N-acetyltransferase activity in the C-terminal GCN5-related N-acetyltransferase domain, which is required for GlcNAc-induced promoter histone acetylation and transcription. Ngs1 is targeted to the promoters of GlcNAc-inducible genes constitutively by the transcription factor Rep1. Ngs1 is conserved in diverse fungi that have GlcNAc catabolic genes. Thus, fungi use Ngs1 as a GlcNAc-sensor and transducer for GlcNAc-induced transcription.

Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation.

BackgroundEpilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. Seizure-induced TLR4/MYD88 signaling plays a critical role in activating microglia and triggering neuron apoptosis. SAHA is a histone deacetylase inhibitor that regulates gene expression by increasing chromatin histone acetylation. In this study, we investigated the role of SAHA in TLR4/MYD88 signaling in a rat seizure model.ResultsSprague–Dawley rats with kainic acid (KA)-induced seizures were treated with SAHA. The expression of TLR4, MYD88, NF-κB P65 and IL-1β in hippocampus was detected at hour 2 and 6 and day 1, 2, and 3 post seizure. SAHA pretreatment increased seizure latency and decreased seizure scores. The expression levels of TLR4, MYD88, NF-κB and IL-1β increased significantly in both activated microglia and apoptotic neurons after KA treatment. The effects were attenuated by SAHA. Chromatin immunoprecipitation assays indicated that the H3 histone acetylation levels significantly decreased while H3K9 levels significantly increased in the KA treatment group. The H3 and H3K9 acetylation levels returned to control levels after SAHA (50 mg/kg) pretreatment. There was a positive correlation between the expression of TLR4 and the acetylation levels of H3K9.ConclusionsHistone deacetylase inhibitor SAHA can suppress seizure-induced TLR4/MYD88 signaling and inhibit TLR4 gene expression through histone acetylation regulation. This suggests that SAHA may protect against seizure-induced brain damage.

Epigenetic regulation contributes to urocortin-enhanced midbrain dopaminergic neuron differentiation.

The production of midbrain dopaminergic (mDA) neurons requires precise extrinsic inductive signals and intrinsic transcriptional cascade at a specific time point in development. Urocortin (UCN) is a peptide of the corticotropin-releasing hormone family that mediates various responses to stress. UCN was first cloned from adult rat midbrain. However, the contribution of UCN to the development of mDA neurons is poorly understood. Here, we show that UCN is endogenously expressed in the developing ventral midbrain (VM) and its receptors are exhibited in Nurr1(+) postmitotic mDA precursors and TH(+) neurons, suggesting possible roles in regulating their terminal differentiation. UCN treatment increased DA cell numbers in rat VM precursor cultures by promoting the conversion of Nurr1(+) precursors into DA neurons. Furthermore, neutralization of secreted UCN with anti-UCN antibody resulted in a reduction in the number of DA neurons. UCN induced an abundance of acetylated histone H3 and enhanced late DA regulator Nurr1, Foxa2, and Pitx3 expressions. Using pharmacological and RNA interference approaches, we further demonstrated that histone deacetylase (HDAC) inhibition and late transcriptional factors upregulation contribute to UCN-mediated DA neuron differentiation. Chromatin immunoprecipitation analyses revealed that UCN promoted histone acetylation of chromatin surrounding the TH promoter by directly inhibiting HDAC and releasing of methyl CpG binding protein 2-CoREST-HDAC1 repressor complex from the promoter, ultimately leading to an increase in Nurr1/coactivators-mediated transcription of TH gene. Moreover, UCN treatment in vivo also resulted in increased DA neuron differentiation. These findings suggest that UCN might contribute to regulate late mDA neuron differentiation during VM development.

Detection of Estrogen Responsive Breast Cancer Circulating Tumor Cells: Assay Development for Anti-Hormone Therapy Resistance

Recent clinical trials with histone deacetylase inhibitors (HDACi) have shown increased progression free survival by re-sensitizing resistant estrogen receptor positive (ER+) breast cancer cells to hormone suppressive therapies (HT). However, these trials lacked a sensitive, specific assay to identify and monitor HDACi/HT sensitive or resistant tumors. We tested detection of ER expression and histone acetylation of chromatin at the growth regulation by estrogen in breast cancer 1 (GREB1) gene, an estrogen-responsive gene involved in ER expression, in circulating tumor cell (CTC) as potential candidate assays for HDACi/HT sensitivity. ER+ and ER- CTC were detected and isolated from breast cancer patient peripheral blood by high speed fluorescence activated cell sorting (FACS) for use in mRNA analysis and anti-acetylated histone-mediated Chromatin Immunoprecipitation (ChIP). cDNA from mRNA and DNA extracted from the ChIP isolates were quantified by real-time PCR for GREB1. CTC isolates from patients who had an ER+ breast cancer primary contained both ER+ and ER- cells. More ER+ than ER- CTC was found in HT sensitive patients compared to HT resistant patients (p = 0.0559). GREB1 was found in acetylated histone chromatin from both ER+ and ER- CTC. The number of ER+ and ER- CTC found in peripheral blood appears to parallel patient outcomes as to their sensitivity to HT. Acetylated histone analysis can detect chromatin containing GREB1 in CTC, suggesting it may be useful as a more specific measure of HDACi effects on breast tumor cells. A larger, longitudinal data set following patients through HT/HDACi trials is needed to confirm these observations and their development for clinical use.

Epigenetic Enhancement of Brain-Derived Neurotrophic Factor Signaling Pathway Improves Cognitive Impairments Induced by Isoflurane Exposure in Aged Rats

Isoflurane-induced cognitive impairments are well documented in animal models; yet, the molecular mechanisms remain largely to be determined. In the present study, 22-month-old male Sprague-Dawley rats received 2 h of 1.5 % isoflurane or 100 % oxygen daily for 3 consecutive days. For the intervention study, the rats were intraperitoneally injected with 1.2 g/kg sodium butyrate 2 h before isoflurane exposure. Our data showed that repeated isoflurane exposure significantly decreased the freezing time to context and the freezing time to tone in the fear conditioning test, which was associated with upregulated histone deacetylase 2, reduced histone acetylation, and increased inflammation and apoptosis in the hippocampus, and impairments of brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) and the downstream signaling pathway phospho-calmodulin-dependent protein kinase and phospho-cAMP response element-binding protein. These results suggest that isoflurane-induced cognitive impairments are associated with the declines in chromatin histone acetylation and the resulting downregulation of BDNF-TrkB signaling pathway. Moreover, the cognitive impairments and the signaling deficits can be rescued by histone deacetylase inhibitor sodium butyrate. Therefore, epigenetic enhancement of BDNF-TrkB signaling may be a promising strategy for reversing isoflurane-induced cognitive impairments.

Systematic analysis of time-series gene expression data on tumor cell-selective apoptotic responses to HDAC inhibitors.

SAHA (suberoylanilide hydroxamic acid or vorinostat) is the first nonselective histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA). SAHA affects histone acetylation in chromatin and a variety of nonhistone substrates, thus influencing many cellular processes. In particularly, SAHA induces selective apoptosis of tumor cells, although the mechanism is not well understood. A series of microarray experiments was recently conducted to investigate tumor cell-selective proapoptotic transcriptional responses induced by SAHA. Based on that gene expression time series, we propose a novel framework for detailed analysis of the mechanism of tumor cell apoptosis selectively induced by SAHA. Our analyses indicated that SAHA selectively disrupted the DNA damage response, cell cycle, p53 expression, and mitochondrial integrity of tumor samples to induce selective tumor cell apoptosis. Our results suggest a possible regulation network. Our research extends the existing research.

Tip60 HAT Activity Mediates APP Induced Lethality and Apoptotic Cell Death in the CNS of a Drosophila Alzheimer's Disease Model

Histone acetylation of chromatin promotes dynamic transcriptional responses in neurons that influence neuroplasticity critical for cognitive ability. It has been demonstrated that Tip60 histone acetyltransferase (HAT) activity is involved in the transcriptional regulation of genes enriched for neuronal function as well as the control of synaptic plasticity. Accordingly, Tip60 has been implicated in the neurodegenerative disorder Alzheimer's disease (AD) via transcriptional regulatory complex formation with the AD linked amyloid precursor protein (APP) intracellular domain (AICD). As such, inappropriate complex formation may contribute to AD-linked neurodegeneration by misregulation of target genes involved in neurogenesis; however, a direct and causative epigenetic based role for Tip60 HAT activity in this process during neuronal development in vivo remains unclear. Here, we demonstrate that nervous system specific loss of Tip60 HAT activity enhances APP mediated lethality and neuronal apoptotic cell death in the central nervous system (CNS) of a transgenic AD fly model while remarkably, overexpression of Tip60 diminishes these defects. Notably, all of these effects are dependent upon the C-terminus of APP that is required for transcriptional regulatory complex formation with Tip60. Importantly, we show that the expression of certain AD linked Tip60 gene targets critical for regulating apoptotic pathways are modified in the presence of APP. Our results are the first to demonstrate a functional interaction between Tip60 and APP in mediating nervous system development and apoptotic neuronal cell death in the CNS of an AD fly model in vivo, and support a novel neuroprotective role for Tip60 HAT activity in AD neurodegenerative pathology.

Epigenetic Enhancement of BDNF Signaling Rescues Synaptic Plasticity in Aging

Aging-related cognitive declines are well documented in humans and animal models. Yet the synaptic and molecular mechanisms responsible for cognitive aging are not well understood. Here we demonstrated age-dependent deficits in long-term synaptic plasticity and loss of dendritic spines in the hippocampus of aged Fisher 344 rats, which were closely associated with reduced histone acetylation, upregulation of histone deacetylase (HDAC) 2, and decreased expression of a histone acetyltransferase. Further analysis showed that one of the key genes affected by such changes was the brain-derived neurotrophic factor (Bdnf) gene. Age-dependent reductions in H3 and H4 acetylation were detected within multiple promoter regions of the Bdnf gene, leading to a significant decrease in BDNF expression and impairment of downstream signaling in the aged hippocampus. These synaptic and signaling deficits could be rescued by enhancing BDNF and trkB expression via HDAC inhibition or by directly activating trkB receptors with 7,8-dihydroxyflavone, a newly identified, selective agonist for trkB. Together, our findings suggest that age-dependent declines in chromatin histone acetylation and the resulting changes in BDNF expression and signaling are key mechanisms underlying the deterioration of synaptic function and structure in the aging brain. Furthermore, epigenetic or pharmacological enhancement of BDNF-trkB signaling could be a promising strategy for reversing cognitive aging.

Application of the histone deacetylase inhibitors for the treatment of endometriosis: histone modifications as pathogenesis and novel therapeutic target

Accumulating evidence suggests that various epigenetic aberrations play definite roles in the pathogenesis of endometriosis. We investigated the histone acetylation status in endometriosis and the application of the histone deacetylase inhibitors (HDACIs) for the treatment of endometriosis. The levels of acetylated histones in the endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) were evaluated. The effects of the HDACIs on cell proliferation, the cell cycle, apoptosis of ECSCs and NESCs, and the expression of genes related to these cellular events were investigated. The effects of HDACIs on histone acetylation in chromatin of the promoter region of the cell cycle regulatory genes in ECSCs were also investigated. The acetylated histone levels were significantly lower in ECSCs than in NESCs (P < 0.025). HDACIs inhibited cell proliferation and induced cell cycle arrest and apoptosis of ECSCs. The effects of HDACIs on NESCs were marginal or weak. These HDACIs induced an accumulation of acetylated histones in total cellular chromatin and in the promoter regions of the p16(INK4a), p21(Waf1/Cip1), p27(Kip1) and cycle checkpoint kinase 2 genes in ECSCs. HDACIs induced the protein expression of these cell cycle regulators and suppressed the protein expression of Bcl-2 and Bcl-X(L) in ECSCs. The present findings demonstrated that aberrant histone modifications are present in endometriosis and that HDACIs reactivated epigenetically silenced genes, resulting in the suppression of cell proliferation, induction of cell cycle arrest and apoptosis of ECSCs. HDACIs are therefore promising agents for the treatment of endometriosis.

Untargeted tail acetylation of histones in chromatin: lessons from yeastThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process.

Dynamic acetylation of lysine residues in the amino-terminal tails of the core histones is functionally important for the regulation of diverse DNA-dependent processes in the nucleus, including replication, transcription, and DNA repair. The targeted and untargeted activities of histone lysine acetylases (KATs) and deacetylases (HDACs) both contribute to the dynamics of chromatin acetylation. While the mechanisms and functional consequences of targeted on histone acetylation are well understood, relatively little is known about untargeted histone acetylation. Here, we review the current understanding of the mechanisms by which untargeted KAT and HDAC activities modulate the acetylation state of nucleosomal histones, focusing on results obtained for H3 and H4 in budding yeast. We also highlight unresolved problems in this area, including the question of how a particular steady-state level of untargeted acetylation is set in the absence of cis-dependent mechanisms that instruct the activity of KATs and HDACs.