HDACs,histone deacetylation and gene transcription: from molecular biology to cancer therapeutics

组蛋白 deacetylases (HDAC ) 并且嘘一乙酰转移 ases (帽子) 是其酶的活动控制蛋白质离氨酸残余的乙酰化状态的二抵抗酶家庭，尤其是在核心 histones.Acetylation 的 N 终端扩展包含的那些嘘通过它对染色质符合构造的影响影响基因表示。Inaddition，几 non-histone 蛋白质由特定的离氨酸残余的乙酰化状态在他们的稳定性或生物功能被调整。HDAC 在大量的生物学过程干涉并且是部分一多每个成员在有它的专业化功能的蛋白质家庭。另外， HDAC 活动紧通过指向的招募， protein-proteininteractions 和 translational 以后修正被控制。房间周期前进，房间幸存和区别的控制在这些酶的最重要的角色之中。因为这些过程被恶意的转变影响， HDAC 禁止者作为反被开发在癌症病人的肿瘤的药和 ares howing 鼓励功效。

Sodium butyrate alleviates deoxynivalenol-induced hepatic cholesterol metabolic dysfunction via RORγ-mediated histone acetylation modification in weaning piglets

Background:Cholesterol is an essential component of lipid rafts in cell plasma membrane,which exerts a hepatoprotective role against mycotoxin exposure in pigs,and cholesterol metabolism is vulnerable to epigenetic histone acetylation.Therefore,our present study aimed to investigate whether a histone deacetylase inhibitor(sodium butyrate [NaBu]) could protect the porcine liver from deoxynivalenol(DON) exposure by modulating cholesterol metabolism.Herein,we randomly divided 28 pigs into four groups,which were fed an uncontaminated basal diet,contaminated diet(4 mg DON/kg),uncontaminated diet supplemented with 0.2% NaBu or 4 mg/kg DON contaminated diet(4 mg DON/kg) supplemented with 0.2% NaBu for 28 d.Results:We found that the serum alanine transaminase(ALT),aspartate transaminase(AST),and alkaline phosphatase(ALP) were all increased in pigs exposed to DON,indicative of significant liver injury.Furthermore,the cholesterol content in the serum of DON-exposed pigs was significantly reduced,compared to the healthy Vehicle group.Transcriptome analysis of porcine liver tissues revealed that the cholesterol homeostasis pathway was highly enriched due to DON exposure.In which we validated by qRT-PCR and western blotting that the cholesterol program was markedly activated.Importantly,NaBu effectively restored parameters associated with liver injury,along with the cholesterol content and the expression of key genes involved in the cholesterol biosynthesis pathway.Mechanistically,we performed a ChIP-seq analysis of H3K27ac and showed that NaBu strongly diminished DON-increased H3K27ac genome-wide enrichment.We further validated that the elevated H3K27ac and H3K9ac occupancies on cholesterol biosynthesis genes were both decreased by NaBu,as determined by ChIP-qPCR analysis.Notably,nuclear receptor RORγ,a novel regulator of cholesterol biosynthesis,was found in the hyperacetylated regions.Again,a remarkable increase of RORγ at both mRNA and protein levels in DON-exposed porcine livers was drastically reduced by NaBu.Consistent with RORγ expression,NaBu also hindered RORγ transcriptional binding enrichments on these activated cholesterol biosynthesis genes like HMGCR,SQLE,and DHCR24.Furthermore,we conducted an in vitro luciferase reporter assay to verify that porcine RORγ directly bonds to the promoters of the above target genes.Conclusions:Collectively,our results demonstrate the utility of the natural product Na Bu as a potential anti-mycotoxin nutritional strategy for regulating cholesterol metabolism via RORγ-mediated histone acetylation modification.

Curcumin inhibits hepatitis B virus infection by downregulating ccc DNA-bound histone acetylation

AIM To investigate the potential effect of curcumin on hepatitis B virus(HBV) covalently closed circular DNA(ccc DNA) and the underlying mechanism.METHODS A Hep G2.2.15 cell line stably transfected with HBV was treated with curcumin, and HBV surface antigen(HBs Ag) and e antigen(HBe Ag) expression levels were assessed by ELISA. Intracellular HBV DNA replication intermediates and ccc DNA were detected by Southern blot and real-time PCR, respectively. The acetylation levels of histones H3 and H4 were measured by Western blot. H3/H4-bound ccc DNA was detected by chromatin immunoprecipitation(Ch IP) assays. The deacetylase inhibitors trichostatin A and sodium butyrate were used to study the mechanism of action for curcumin. Additionally, short interfering RNAs(si RNAs) targeting HBV were tested along with curcumin.RESULTS Curcumin treatment led to time-and dose-dependent reductions in HBs Ag and HBe Ag expression and significant reductions in intracellular HBV DNA replication intermediates and HBV ccc DNA. After treatment with 20 μmol/L curcumin for 2 d, HBs Ag and ccc DNA levels in Hep G2.2.15 cells were reduced by up to 57.7%(P < 0.01) and 75.5%(P < 0.01), respectively, compared with levels in non-treated cells. Meanwhile, time-and dose-dependent reductions in the histone H3 acetylation levels were also detected upon treatment with curcumin, accompanied by reductions in H3-and H4-bound ccc DNA. Furthermore, the deacetylase inhibitors trichostatin A and sodium butyrate could block the effects of curcumin. Additionally, transfection of si RNAs targeting HBV enhanced the inhibitory effects of curcumin.CONCLUSION Curcumin inhibits HBV gene replication via downregulation of ccc DNA-bound histone acetylation and has the potential to be developed as a ccc DNA-targeting antiviral agent for hepatitis B.

Histone acetylation of the htr3a gene in the prefrontal cortex of Wistar rats regulates ethanol-seeking behavior

Previous reports showed that decreased histone deacetylase activity significantly potentiated the rewarding effects of psychostimulants, and that encoding of the 5-HT3 receptor by the htr3a gene was related to ethanol-seeking behavior. However, the effects of a histone deacetylase inhibitor on ethanol-seeking behavior and epigenetic regulation of htr3a mRNA expression after chronic ethanol exposure are not fully understood. Using quantitative reverse transcription-polymerase chain reaction and chromatin immunoprecipitation analysis, we investigated the effects of chronic ethanol exposure and its interaction with a histone deacetylase inhibitor on histone-acetylation-mediated changes in htr3a mRNA expression in the htr3a promoter region. The conditioned place preference procedure was used to evaluate ethanol-seeking behavior. Chronic exposure to ethanol effectively elicited place conditioning. In the prefrontal cortex, the acetylation of H3K9 and htr3a mRNA expression in the htr3a promoter region were significantly higher in the ethanol group than in the saline group. The histone deacetylase inhibitor sodium butyrate potentiated the effects of ethanol on htr3a mRNA expression and enhanced ethanol-induced conditioned place preferences. These results suggest that ethanol upregulates htr3a levels through mechanisms involving H3K9 acetylation, and that histone acetylation may be a therapeutic target for treating ethanol abuse.

Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer

BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.

Induction of Apoptosis and Acetylation of Histone H3 and H4 by Arctigenin in the Human Melanoma Cell Line SK-MEL-28

Cutaneous melanoma is one of the most aggressive forms of skin cancer. Arctigenin, one of the major bioactive compo-nents of Arctii Fructus, has been reported to exhibit antioxidant, antitumor and anti-inflammatory activities. In the pre-sent study, we investigated the effect of arctigenin on induction of apoptosis in highly metastatic SK-MEL-28 human melanoma cells. Arctigenin inhibited growth of SK-MEL-28 cells in a dose-dependent manner. Treatment of SK-MEL-28cells with arctigenin caused cleavage of caspases 3, 7 and 9, and poly (ADP-ribose) polymerase in a dose-dependent manner. Furthermore, acetylation of histone H3 and H4 in the SK-MEL-28 cells was dramatically increased by arctigenin treatment. Collectively, these findings indicate that arctigenin-induces apoptosis of SK-MEL-28 melanoma cells via activation of caspases and histone acetylation.

Histone acetylation and its role in embryonic stem cell differentiation

The understanding of mechanisms leading to cellular differentiation is the main aim of numerous studies.Accessibility of DNA to transcription factors depends on local chromatin structure and chromatin compaction inhibits gene transcription.Histone acetylation correlates with an open chromatin structure and increased gene expression.Gene transcription levels are changed in early embryonic stem cells differentiation in a tissuespecific manner and epigenetic marks are modified,including increased global acetylation levels.Manipulation of histone deacetylases activity might be an interesting tool to generate populations of specific cell types for transplantation purposes.Thus,this review aims to show recent findings on histone acetylation,a post translational modif ication and its manipulation in embryonic stem cells differentiation.

Histone deacetylase inhibitors as a novel therapeutic approach for pheochromocytomas and paragangliomas

Epigenetic mechanisms,such as DNA methylation and histone modifications(e.g.,acetylation and deacetylation),are strongly implicated in the carcinogenesis of various malignancies.During transcription,the expression and functionality of coding gene products are altered following the histone acetylation and deacetylation.These processes are regulated by histone acetyltransferases(HATs)and histone deacetylases(HDACs),respectively.HDAC inhibitors(HDACis)have been developed as promising therapeutic agents,to limit exposure to traditional and toxic chemotherapies and offer more alternatives for some specific malignant diseases with limited options.Mechanistically,these agents affect many intracellular pathways,including cell cycle arrest,apoptosis and differentiation,and their mechanism of action mainly depends on the type of cancer.Currently,five HDACis have been approved for the treatment of several hematological malignancies(e.g.,T-cell lymphoma subtypes and multiple myeloma);while,many of them are tested for further therapeutic indications in solid tumors(e.g.,colorectal,thyroid,breast,lung and pancreatic cancer).Herein,we review the literature and gather all available evidence,from in vitro and in vivo data to clinical trial results,that recognizes the antitumor activity of HDACis on pheochromocytomas and paragangliomas;and supports their clinical implementation in the treatment of these rare neuroendocrine tumors at metastatic setting.

Dynamic profiles of DNA methylation and the interaction with histone acetylation during fiber cell initiation of Gossypium hirsutum

Background:Fiber,as the main product of cotton,provides main raw material for the textile industry.Many key factors have been revealed a significant role in fiber cell development including Myb proteins,phytohormones,fatty acid metabolites,and epigenetic modifications.DNA methylation is one of the important epigenetic modifications to regulate plant development and responses to abiotic or biotic stimuli.In general,DNA methylation consisting of 5mC and 6mA regulates the chromatin structure and gene transcription to affect plant development,however,the detailed role and underlying mechanism of DNA methylation in the fiber development of cotton are yet vague.Results:Here,systematical study of the 5mC and 6mA DNA methylation profiles during the fiber initiation period of Xu142 and its glabrous mutant Xu142fl represented a clear alteration of global DNA methylation associated with fiber cell initiation.Then,the genome-wide identification of genes responsible for methylation regulation at the fifth carbon of cytosine and the sixth carbon of adenine of DNA was operated in Gossypium hirsutum.As a result,13,10,6,and 17 genes were identified for 5mC methylation,5mC demethylation,6mA methylation,and 6mA demethylation,respectively.We then investigated the tissue expression pattern of all these genes,and some genes showed higher expression levels in fiber initiation,among which some displayed a significant change in transcription between Xu142 and Xu142fl.The possible interaction between histone acetylation and DNA methylation in fiber initiation through in vitro culture was studied by dot blot,and the results showed that repressed histone deacetylation by Trichostatin A(TSA)inhibited the global DNA methylation,and some causal genes(e.g.,GhDMT13,GhDAMT2,GhALKBH12,GhDM7)were also identified.Conclusions:In this study,all the findings indicated the interplay between histone acetylation and DNA methylation,supporting their important roles and providing precious clues for the epigenetic modifications associated with DNA methylation in the fiber development of cotton.

Effects of histone acetylation and DNA methylation on p21^(WAF1)regulation

Cell cycle progression is regulated by interactions betweencyclins and cyclin-dependent kinases (CDKs). p21wAF1 is oneof the CIP/KIP family which inhibits CDKs activity. Increasedexpression of p21WAF1 may play an important role in thegrowth arrest induced in transformed calls. Although thestability of the p21wAF1 mRNA could be altered by differentsignals, cell differentiation and numerous influencingfactors. However, recent studies suggest that two knownmechanisms of epigenesis, i. e. gene inactivation bymethylation in promoter region and changes to an inactivechromatin by histone deacetylation, seem to be the bestcandidate mechanisms for inactivation of p21WAF1. To date,almost no coding region p21wAF1 mutations have been foundin tumor cells, despite extensive screening of hundreds ofvarious tumors. Hypermethylation of the p21WAF1 promoterregion may represent an alternative mechanism by which thep21WAF1/ClPl gene can be inactivated. The reduction of cellularDNMT protein levels also induces a corresponding rapidincrease in the cell cycle regulator p21wAF1 proteindemonstrating a regulatory link between DNMT and p21WAF1which is independent of methylation of DNA. Both histonehyperacetylation and hypoacetylation appear to be importantin the carcinoma process, and induction of the p21WAF1 geneby histone hyperacetylation may be a mechanism by whichdietary fiber prevents carcinogenesis. Here, we review theinfluence of histone acetylation and DNA methylation onp21WAF1 transcription, and affection of pathways or factorsassociated such as p53, E2A, Sp1 as well as several histonedeacetylation inhibitors.

Involvement of chromatin and histone acetylation in the regulation of HIV-LTR by thyroid hormone receptor

The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR Promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFkB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase- dependent manner.

Curcumin-induced Histone Acetylation in Malignant Hematologic Cells

This study investigated the inhibitory effects of curcumin on proliferation of hematological malignant cells in vitro and the anti-tumor mechanism at histone acetylation/histone deacetylation levels. The effects of curcumin and histone deacetylase inhibitor trichostatin A （TSA） on the growth of Raji cells were tested by MTT assay. The expression of acetylated histone-3 （H3） in Raji, HL60 and K562 cells, and peripheral blood mononuclear cells （PBMCs） treated with curcumin or TSA was detected by immunohistochemistry and FACS. The results showed curcumin inhibited pro- liferation of Raji cells significantly in a time- and dose-dependent fashion, while exhibited low toxicity in PBMCs. Curcumin induced up-regulation of the expression of acetylated H3 dose-dependently in all malignant cell lines tested. In conclusion, curcumin inhibited proliferation of Raji cells selectively, enhanced the level of acetylated H3 in Raji, HL60, and K562 cells, which acted as a histone deacetylase inhibitor like TSA. Furthermore, up-regulation of H3 acetylation may play an important role in regulating the proliferation of Raji cells.

Effects of Triptolide on Histone Acetylation and HDAC8 Expression in Multiple Myeloma in vitro

Objective： Multiple myeloma is a kind of malignant plasma cell disease that originated from B lymphocyte and secrete great amount of monoclonal immunoglobulin. It is still one of the refractory diseases at present. Numerous studies show that there is an intensive relationship between the disequilibrium of histone acetylation and the occurance of multiple myeloma. Here we investigated the effect of triptolide（TPL） on the proliferation, apoptosis, histone H3 and H4 acetylation and expression of histone deacetylase 8 （HDAC8） in vitro, to explore its anti- myeloma mechanism. Methods： The effect of triptolide on the growth of RPMI8226 was studied by 3-（4,5-Dimethyl-2-thiazolyl） -2,5-diphenyl-2H-tetrazolium（MTT） assay. Apoptosis was detected by Hoechst 33258 staining. The protein expressions of acetyl-histone H3 and H4 were determined by Western blot, and the expression of HDAC8 was assessed by RT-PCR, Western blot and confocal microscopy. Results： Triptolide inhibited the proliferation of RPMI8226 and induced apoptosis in a time- and dosedependent manner. The 36h IC50 value was （105.370 ± 0.189）nmol/L. Triptolide increased the acetylation of histone H3 and H4 greatly. Furthermore, triptolide significantly down-regulated the mRNA and protein expression of HDAC8. Conclusion： Triptolide can inhibit proliferation and induce apoptosis of RPMI8226 significantly. Triptolide reduces the expression of HDAC8 in order to increase the histone H3 and H4 acetylation, which is possibly the anti-myeloma mechanism of triptolide.

Regulation of Histone Acetylation and Apoptosis by Trichostatin in HL-60 Cells

Summary: In order to examine the strong anticancer action and low toxicity of Trichostatin A (TSA), the effect of TSA was examined on the growth inhibition, acetylation of histone H_3 and apoptosis in HL-60 cells by employing MTT, immunocytochemical techniques, and Annexin-V-FITC/PI assay. Our results showed that TSA could inhibit proliferation of HL-60 cells in a time-and dose-dependent manner, and the IC_~50 at the 36th h was 100 ng/ml. The apoptosis-inducing effect of TSA on HL-60 cells was also time-and dose-dependent. But it didn't demonstrate apparent apoptosis induction in NPBMNCs within specific dose and time range. Both of the acetylation of histone H_3 in HL-60 cells and NPBMNCs increased significantly (P<0.05) after treated with 100 ng/ml TSA for 4 h. However, there was no significant differences between the two groups (P>0.05). It is concluded that TSA can inhibit growth and induce apoptosis of HL-60 cells in a time-and dose-dependent manner, and is able to selectively induce apoptosis in HL-60 cells but does not respond in NPBMNCs under the same conditions. The difference of TSA between HL-60 cells and NPBMNCs can't be explained by the regulation of histone acetylation.

Reducing histone acetylation rescues cognitive deficits in mouse model of fragile X syndrome

Fragile X syndrome(FXS)is the most prevalent inherited intellectual disability,resulting from a loss of fragile X mental retardation protein(FMRP).Patients with FXS suffer lifelong cognitive disabilities,but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FXS is not fully understood.Here,we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitinationmediated degradation of histone deacetylase HDAC1 in adult hippocampal neural stem cells(NSCs).Consequently,FMRPdeficient NSCs exhibit elevated histone acetylation and age-related NSC depletion,leading to cognitive impairment in mature adult mice.Reducing histone acetylation rescues both neurogenesis and cognitive deficits in mature adult FMRPdeficient mice.Our work reveals a role for FMRP and histone acetylation in cognition and presents a potential novel ther⁃apeutic strategy for treating adult FXS patients.

Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.

Effects of histone deacetylase inhibitors on transcriptional regulation of the hsp70 gene in Drosophila

Histone acetyltransferases/deacetylases 贡献激活或在由修改染色质的结构的抄写的激活。这里，我们检验了效果嘘在果蝇的 hsp70 基因 transcriptional 规定上的一个 deacetylase 禁止者(HDI ) ， trichostatin A，和钠丁酸盐。染色质免疫降水试金表明 HDI 处理导致了 hyperacetylation 嘘在倡导者和 hsp70 基因的抄录区域的一 H3，增加了热吃惊因素的可接近性指向热吃惊元素，并且支持了 RNA 聚合酶调停 II 的抄写。而且，量的即时 PCR 证实导致 HDI 的 hyperacetylation 嘘一 H3 提高了两个基础并且 hsp70 mRNA 的可诱导的表示水平。另外， acetylation 水平嘘在倡导者的一 H3 在热吃惊的时间之上展出了一个波动的变化。这些试验性的数据含有一个原因的连接在之间嘘一 acetylation 和在果蝇的 hsp70 基因的提高的抄写开始。

Expression of p21^(WAF1) is related to acetylation of histone H3 in total chromatin in human coiorectai cancer

瞄准：探索在乙酰化作用之间的关系嘘在全部的染色质的和在人的 p21WAF1 表示规定渲染表面的癌。方法：我们分析了肿瘤的表示压制或由 RT-PCR 的基因 p21WAF1 mRNA 或真实 -- 在表面的癌的织物，相应帕拉癌的织物和正常渲染的颜色的 33 件样品的时间 PCR 表面的粘膜，并且也检验了乙酰 ated 的水平嘘在全部的染色质使用西方的弄污的一 H3。结果：p21WAF1 mRNA 的表示水平是显著地更低的在比在帕拉从 33 个病人渲染表面的癌的织物 -- 癌的织物和正常渲染表面的粘膜(2377.95 +/- 865.80 对 3216.58 +/- 1149.42 和 3541.61 +/- 1433.17 分别地， P 【 0.01 ) 。另外，当 p21WAF1 mRNA 表示是 undectectable 时或在很低级(50%不到那在邻近的织物和正常渲染表面的粘膜)在所有纸巾，乙酰 ated 的水平嘘在颜色的一 H3 表面的癌的织物在相应帕拉癌的织物是比那显著地低的，正常在七中的五个渲染表面的粘膜(71.43%)盒子。在颜色的 p21WAF1 的 transcriptional 水平表面的癌可能没与它的生物行为被联系。结论：p21WAF1 抄写的下面规定涉及颜色的肿瘤发生和发展表面的癌。在颜色的 p21WAF1 mRNA 的下面表示表面的癌可能与被联系嘘在染色质然而并非与生物行为的一 hypoacetylation。

Proportions of acetyl-histone-positive hepatocytes indicate the functional status and prognosis of cirrhotic patients

AIM:To investigate whether the proportions of acetylhistone-positive hepatocytes could be used as markers of deteriorating liver function.METHODS:In total,611 cirrhotic cases from 3701 patients who were diagnosed during the past 15 years were screened,and 152 follow-up cases were selected.Paraffin tissue microarray was prepared for immunohistochemistry to examine acetyl-histone expression.The proportions of positive hepatocytes were recorded,and their correlations to clinical and laboratory indicators were analyzed statistically.RESULTS:The proportions of H2AK5ac+,H3K9/K14ac+ and H3K27ac+ hepatocytes gradually increased with deteriorating liver function and with increasing levels of serum markers of liver injury.In the follow-up cases,patients with > 70% H2AK5ac+,H3K9/K14ac+ or H3K27ac+ hepatocytes had statistically lower survival rates(P < 0.05).Furthermore,> 70% H2AK5ac+ or H3K27ac+ hepatocytes were strong independent predictors of overall survival(P < 0.05).CONCLUSION:The proportions of acetyl-histonepositive hepatocytes are closely associated with the liver function and prognosis of cirrhotic patients.

Histone acetyltransferase GCN5 interferes with the miRNA pathway in Arabidopsis

MicroRNAs (miRNA ) 指导在基因表示的一个重要角色在植物为到环境条件的发展进程和回答要求了的顺序特定的 posttranscriptional 基因 silencing 玩。然而，很少对 transcriptional 和 miRNA 表示的 posttranscriptional 规定被知道。Histone acetylation 在染色质改变起一个重要作用并且为基因激活被要求。由在 Arabidopsis 的异种分析 miRNAs 和相应主要 miRNAs 的子集的累积，我们显示出那 histone acetyltransferase GCN5 (一般控制非镇压的 protein5 )在 miRNA 上有一般压抑的效果生产，当它为一个子集的表示被要求时(例如压力可诱导) MIRNA 基因。在 miRNA 生产的 GCN5 的一般否定功能多半通过象 DICER LIKE1 (DCL1 ) 那样的 miRNA 机械基因的间接压抑被完成，有锯齿(SE ) ，偏下性的 LEAVES1 (HYL1 ) 和 ARGONAUTE1 (AGO1 ) 。染色质 immunoprecipitation 试金表明 GCN5 指向到 MIRNA 基因的一个子集并且为在这些 loci 的 histone H3 离氨酸 14 的 acetylation 被要求。而且，由 trichostatin 的 histone deacetylation 的抑制一个处理或在 histone deacetylase，基因异种损害了某些 miRNAs 的累积。这些数据一起建议 Arabidopsis GCN5 在 transcriptional 和 posttranscriptional 层次防碍 miRNA 小径， histone acetylation/deacetylation 是涉及 miRNA 的规定的 epigenetic 机制生产。