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Trichostatin A Selectively Suppresses the Cold-Induced Transcription of the ZmDREB1 Gene in Maize  [PDF]
Yong Hu,Lu Zhang,Lin Zhao,Jun Li,Shibin He,Kun Zhou,Fei Yang,Min Huang,Li Jiang,Lijia Li
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022132
Abstract: Post-translational modifications of histone proteins play a crucial role in responding to environmental stresses. Histone deacetylases (HDACs) catalyze the removal of an acetyl group from histones and are generally believed to be a transcriptional repressor. In this paper, we report that cold treatment highly induces the up-regulation of HDACs, leading to global deacetylation of histones H3 and H4. Treatment of maize with the HDAC inhibitor trichostatin A (TSA) under cold stress conditions strongly inhibits induction of the maize cold-responsive genes ZmDREB1 and ZmCOR413. However, up-regulation of the ZmICE1 gene in response to cold stress is less affected. The expression of drought and salt induced genes, ZmDBF1 and rab17, is almost unaffected by TSA treatment. Thus, these observations show that HDACs may selectively activate transcription. The time course of TSA effects on the expression of ZmDREB1 and ZmCOR413 genes indicates that HDACs appear to directly activate the ZmDREB1 gene, which in turn modulates ZmCOR413 expression. After cold treatment, histone hyperacetylation and DNA demethylation occurs in the ICE1 binding region, accompanied by an increase in accessibility to micrococcal nuclease (MNase). The two regions adjacent to the ICE1 binding site remain hypoacetylated and methylated. However, during cold acclimation, TSA treatment increases the acetylation status and accessibility of MNase and decreases DNA methylation at these two regions. However, TSA treatment does not affect histone hyperacetylation and DNA methylation levels at the ICE1 binding regions of the ZmDREB1 gene. Altogether, our findings indicate that HDACs positively regulate the expression of the cold-induced ZmDREB1 gene through histone modification and chromatin conformational changes and that this activation is both gene and site selective.
Trichostatin A effects on gene expression in the protozoan parasite Entamoeba histolytica
Gretchen M Ehrenkaufer, Daniel J Eichinger, Upinder Singh
BMC Genomics , 2007, DOI: 10.1186/1471-2164-8-216
Abstract: In order to identify the genome-wide effects of histone acetylation in regulating E. histolytica gene expression, we used whole-genome expression profiling of parasites treated with SCFA and Trichostatin A (TSA). Despite significant changes in histone acetylation patterns, exposure of parasites to SCFA resulted in minimal transcriptional changes (11 out of 9,435 genes transcriptionally regulated). In contrast, exposure to TSA, a more specific inhibitor of histone deacetylases, significantly affected transcription of 163 genes (122 genes upregulated and 41 genes downregulated). Genes modulated by TSA were not regulated by treatment with 5-Azacytidine, an inhibitor of DNA-methyltransferase, indicating that in E. histolytica the crosstalk between DNA methylation and histone modification is not substantial. However, the set of genes regulated by TSA overlapped substantially with genes regulated during parasite development: 73/122 genes upregulated by TSA exposure were upregulated in E. histolytica cysts (p-value = 6 × 10-53) and 15/41 genes downregulated by TSA exposure were downregulated in E. histolytica cysts (p-value = 3 × 10-7).This work represents the first genome-wide analysis of histone acetylation and its effects on gene expression in E. histolytica. The data indicate that SCFAs, despite their ability to influence histone acetylation, have minimal effects on gene transcription in cultured parasites. In contrast, the effect of TSA on E. histolytica gene expression is more substantial and includes genes involved in the encystation pathway. These observations will allow further dissection of the effects of histone acetylation and the genetic pathways regulating stage conversion in this pathogenic parasite.Regulation of gene expression is a complex process controlled by sequence-specific DNA binding proteins, modulation of chromatin structure, and post-transcriptional modifications. In recent years, increased attention has been given to the role of epigenetic mecha
Deacetylation of H4-K16Ac and heterochromatin assembly in senescence
Kévin Contrepois, Jean-Yves Thuret, Régis Courbeyrette, Fran?ois Fenaille, Carl Mann
Epigenetics & Chromatin , 2012, DOI: 10.1186/1756-8935-5-15
Abstract: We found that both deacetylation of H4-K16Ac and expression of HMGA1/2 can contribute to DNA compaction during senescence. SIRT2, an NAD-dependent class III histone deacetylase, contributes to H4-K16Ac deacetylation and DNA compaction in human fibroblast cell lines that assemble striking senescence-associated heterochromatin foci (SAHFs). Decreased H4-K16Ac was observed in both replicative and oncogene-induced senescence of these cells. In contrast, this mechanism was inoperative in a fibroblast cell line that did not assemble extensive heterochromatin during senescence. Treatment of senescent cells with trichostatin A, a class I/II histone deacetylase inhibitor, also induced rapid and reversible decondensation of SAHFs. Inhibition of DNA compaction did not significantly affect the stability of the senescent state.Variable DNA compaction observed during senescence is explained in part by cell-type specific regulation of H4 deacetylation and HMGA1/2 expression. Deacetylation of H4-K16Ac during senescence may explain reported decreases in this mark during mammalian aging and in cancer cells.Genomic DNA in eukaryotes is packaged into chromatin. The histones and non-histone proteins of chromatin compact the DNA and govern its accessibility to enzymes during transcription, replication, repair and recombination. Poorly transcribed regions of the genome are typically found in highly compacted DNA as heterochromatin, whereas transcribed sequences are found in the more accessible euchromatin [1]. Post-translational modifications of histones represent an important mechanism modulating the accessibility of chromatin and contributing to the recruitment of other proteins to chromatin [2]. Histones are extensively modified principally by acetylation, methylation, ubiquitylation, and phosphorylation. Euchromatin is enriched in histones acetylated at lysine residues. Acetylation of H4-K16 plays a particularly important, evolutionarily conserved role in regulating chromatin compacti
Development of an Oral Form of Azacytidine: Triacetyl-5-Azacytidine  [PDF]
Amy Ziemba,Eugene Hayes,Burgess B. Freeman III,Tao Ye,Giuseppe Pizzorno
Chemotherapy Research and Practice , 2011, DOI: 10.1155/2011/965826
Abstract: Myelodysplastic syndromes (MDSs) represent a group of incurable stem-cell malignancies which are predominantly treated by supportive care. Epigenetic silencing through promoter methylation of a number of genes is present in poor-risk subtypes of MDS and often predicts transformation to acute myelogenous leukemia (AML). Azacitidine and decitabine, two FDA-approved DNA methyltransferase (DNMT) inhibitors, are able to improve overall response although their oral bioavailability complicates their clinical use. This study evaluated 2,3,5-triacetyl-5-azacitidine (TAC) as a potential prodrug for azacitidine. The prodrug demonstrated significant pharmacokinetic improvements in bioavailability, solubility, and stability over the parent compound. In vivo analyses indicated a lack of general toxicity coupled with significantly improved survival. Pharmacodynamic analyses confirmed its ability to suppress global methylation in vivo. These data indicate that esterified nucleoside derivatives may be effective prodrugs for azacitidine and encourages further investigation of TAC into its metabolism, activity, and possible clinical evaluation.
Development of an Oral Form of Azacytidine: Triacetyl-5-Azacytidine  [PDF]
Amy Ziemba,Eugene Hayes,Burgess B. Freeman III,Tao Ye,Giuseppe Pizzorno
Chemotherapy Research and Practice , 2011, DOI: 10.1155/2011/965826
Abstract: Myelodysplastic syndromes (MDSs) represent a group of incurable stem-cell malignancies which are predominantly treated by supportive care. Epigenetic silencing through promoter methylation of a number of genes is present in poor-risk subtypes of MDS and often predicts transformation to acute myelogenous leukemia (AML). Azacitidine and decitabine, two FDA-approved DNA methyltransferase (DNMT) inhibitors, are able to improve overall response although their oral bioavailability complicates their clinical use. This study evaluated 2  , 3  , 5  -triacetyl-5-azacitidine (TAC) as a potential prodrug for azacitidine. The prodrug demonstrated significant pharmacokinetic improvements in bioavailability, solubility, and stability over the parent compound. In vivo analyses indicated a lack of general toxicity coupled with significantly improved survival. Pharmacodynamic analyses confirmed its ability to suppress global methylation in vivo. These data indicate that esterified nucleoside derivatives may be effective prodrugs for azacitidine and encourages further investigation of TAC into its metabolism, activity, and possible clinical evaluation. 1. Introduction Currently, it is estimated that between 12,000 and 20,000 new cases of MDS are diagnosed each year in the United States. Although MDS can affect all ages, the highest prevalence occurs in those over 60 years of age [1, 2]. Much of the population has indolent forms of MDS, making it one of the most prevalent hematologic malignancies of older adults. MDS represents a heterogeneous group of hematopoietic disorders which are derived from an abnormal multipotent progenitor cell and are characterized by hyperproliferative bone marrow, cellular dysplasia, and ineffective hematopoiesis [3]. Morbidity and mortality result from anemia, bleeding, and infection, along with transformation to acute myelogenous leukemia (AML) in approximately one-third of patients [4, 5]. The basis of therapy is supportive care, including red blood cell or platelet transfusions and treatment of infections. Stem-cell transplantation remains the only chance for cure, but it is associated with significant treatment-related morbidity and mortality and is generally restricted to patients <60 years of age [6]. Similar limitations exist for the use of high dose chemotherapy. Given the limitations of existing therapies, there is a clear need for additional therapeutic options for patients with MDS. Cancer cells are characterized by abnormal DNA methylation patterns, and DNA hypermethylation is suspected of being involved in MDS progression and
Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis
Heather R Pelzel, Cassandra L Schlamp, Robert W Nickells
BMC Neuroscience , 2010, DOI: 10.1186/1471-2202-11-62
Abstract: Histone deacetylase 3 (HDAC3) translocates to the nuclei of dying cells shortly after lesion of the optic nerve and is associated with an increase in nuclear HDAC activity and widespread histone deacetylation. H4 in promoters of representative genes was rapidly and indiscriminately deacetylated, regardless of the gene examined. As apoptosis progressed, H4 of silenced genes remained deacetylated, while H4 of newly activated genes regained, or even increased, its acetylated state. Inhibition of retinal HDAC activity with trichostatin A (TSA) was able to both preserve the expression of a representative RGC-specific gene and attenuate cell loss in response to optic nerve damage.These data indicate that histone deacetylation plays a central role in transcriptional dysregulation in dying RGCs. The data also suggests that HDAC3, in particular, may feature heavily in apoptotic gene silencing.Intrinsic apoptosis in neurons culminates in BAX activation and translocation to the mitochondria, the release of cytochrome c, and the activation of the caspase cascade. BAX translocation marks the committed step of the cell death process [1]. Therefore, investigation of the apoptotic pathway prior to BAX involvement is an important element of developing strategies to intervene in neuronal cell death.An early event in apoptosis is silencing of normal gene expression. In addition to this, new transcription, required for apoptosis, is activated. This change in transcriptional profile occurs in several models of neurodegeneration, including Huntington's Disease, Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, spinocerebellar ataxia type 3, and the optic neuropathy glaucoma [2-10]. In glaucoma, retinal ganglion cells (RGCs) execute a typical intrinsic apoptotic program. Changes in transcription of several genes in injured RGCs have been shown in experimental glaucoma and after acute injury to the optic nerve. Genes that decrease in expression in RGCs include severa
Structural Biology of Human H3K9 Methyltransferases  [PDF]
Hong Wu,Jinrong Min,Vladimir V. Lunin,Tatiana Antoshenko,Ludmila Dombrovski,Hong Zeng,Abdellah Allali-Hassani,Valérie Campagna-Slater,Masoud Vedadi,Cheryl H. Arrowsmith,Alexander N. Plotnikov,Matthieu Schapira
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008570
Abstract: SET domain methyltransferases deposit methyl marks on specific histone tail lysine residues and play a major role in epigenetic regulation of gene transcription. We solved the structures of the catalytic domains of GLP, G9a, Suv39H2 and PRDM2, four of the eight known human H3K9 methyltransferases in their apo conformation or in complex with the methyl donating cofactor, and peptide substrates. We analyzed the structural determinants for methylation state specificity, and designed a G9a mutant able to tri-methylate H3K9. We show that the I-SET domain acts as a rigid docking platform, while induced-fit of the Post-SET domain is necessary to achieve a catalytically competent conformation. We also propose a model where long-range electrostatics bring enzyme and histone substrate together, while the presence of an arginine upstream of the target lysine is critical for binding and specificity.
Genome-Wide Alteration of Histone H3K9 Acetylation Pattern in Mouse Offspring Prenatally Exposed to Arsenic  [PDF]
Andrea A. Cronican, Nicholas F. Fitz, Alexis Carter, Muzamil Saleem, Sruti Shiva, Aaron Barchowsky, Radosveta Koldamova, Jonathan Schug, Iliya Lefterov
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053478
Abstract: Chronic exposure to arsenic in drinking water, especially in utero or perinatal exposure, can initiate neurological and cognitive dysfunction, as well as memory impairment. Several epidemiological studies have demonstrated cognitive and learning deficits in children with early exposure to low to moderate levels of arsenic, but pathogenic mechanisms or etiology for these deficits are poorly understood. Since in vivo studies show a role for histone acetylation in cognitive performance and memory formation, we examined if prenatal exposure to arsenic causes changes in the epigenomic landscape. We exposed C57Bl6/J mice to 100 μg/L arsenic in the drinking water starting 1 week before conception till birth and applied chromatin immunoprecipitation followed by high-throughput massive parallel sequencing (ChIP-seq) to evaluate H3K9 acetylation pattern in the offspring of exposed and control mice. Arsenic exposure during embryonic life caused global hypo-acetylation at H3K9 and changes in functional annotation with highly significant representation of Krüppel associated box (KRAB) transcription factors in brain samples from exposed pups. We also found that arsenic exposure of adult mice impaired spatial and episodic memory, as well as fear conditioning performance. This is the first study to demonstrate: a) genome wide changes in H3K9 acetylation pattern in an offspring prenatally exposed to arsenic, and b) a connection between moderate arsenic exposure and cognitive impairment in adult mice. The results also emphasize the applicability of Next Generation Sequencing methodology in studies aiming to reveal the role of environmental factors, other than dietary restriction, in developmental reprogramming through histone modifications during embryonic development.
Gastric cancer cell lines induced by trichostatin A  [cached]
Xiao-Ming Zou, Yun-Long Li, Hao Wang, Wu Cui, Xiao-Lin Li, Song-Bin Fu, Hong-Chi Jiang
World Journal of Gastroenterology , 2008,
Abstract: AIM: To explore the effect of trichostatin A (TSA) on apoptosis and acetylated histone H3 levels in gastric cancer cell lines BGC-823 and SGC-7901.METHODS: The effect of TSA on growth inhibition and apoptosis was examined by MTT, fluorescence microscopy and PI single-labeled flow cytometry. The acetylated histone H3 level was detected by Western blot.RESULTS: TSA induced apoptosis in gastric cancer cell lines BGC-823 and SGC-7901 was in a dose and time-dependent manner. Apoptotic cells varied significantly between TSA treated groups (37.5 ng/mL 72 h for BGC-823 cell line and 75 ng/mL 72 h for SGC-7901 cell line) and control group (0.85 ± 0.14 vs 1.14 ± 0.07, P = 0.02; 0.94 ± 0.07 vs 1.15 ± 0.06, P = 0.02). Morphologic changes of apoptosis, including nuclear chromatin condensation and fluorescence strength, were observed under fluorescence microscopy. TSA treatment in BGC-823 and SGC-7901 cell lines obviously induced cell apoptosis, which was demonstrated by the increased percentage of sub-G1 phase cells, the reduction of G1-phase cells and the increase of apoptosis rates in flow cytometric analysis. The result of Western blot showed that the expression of acetylated histone H3 increased in BGC-823 and SGC-7901 TSA treatment groups as compared with the control group.CONCLUSION: TSA can induce cell apoptosis in BGC-823 and SGC-7901 cell lines. The expression of acetylated histone H3 might be correlated with apoptosis.
Synthesis and Antiproliferative Activities of 5-Azacytidine Analogues in Human Leukemia Cells  [PDF]
Gang Guo,Gang Li,Dan Liu,Qian-Jiao Yang,Yu Liu,Yong-Kui Jing,Lin-Xiang Zhao
Molecules , 2008, DOI: 10.3390/molecules13071487
Abstract: Twenty-six 5-azacytidine analogues have been synthesized, including 4-amino- 6-alkyl-1-pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 1a-j, 6-amino-4-alkyl/aryl-1- pyranosyl/ribofuranosyl-1,3,5-triazin-2(1H)-ones 2a-f and 4-amino-6-alkyl-1,3,5-triazin-2- yl-1-thio-pyranosides/ribofuranosides 3a-j. The antiproliferative activities of these synthetic analogues were investigated in human leukemia HL-60 cells. Ribofuranosyl Snucleoside 3a, a bioisostere of 5-azacytidine, had a similar antiproliferative ability as that of the latter. Introduction of a methyl at the 6 position of 5-azacytidine and/or replacement of the ribofuranosyl moiety with pyranosyl sugars or disaccharides significantly decreased the antiproliferative activities of the 5-azacytidine derivatives. Several compounds with the replacement of pyranosyl sugars enhanced all-trans retinoic acid-induced differentiation ability in human leukemia HL-60 cells.
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