Global alterations in histone acetylation levels have been observed in both normal and cancer cells and can be prognostic of clinical outcome. However, unlike site-specific acetylation changes that can affect transcription of particular genes, the reason for genome-wide changes has been less clear. Because acetyl-coA molecules required for histone acetylation and acetate anions generated by histone deacetylation are required for many metabolic processes, McBrian and colleagues hypothesized that metabolic or physiologic cues might affect global histone acetylation levels. Systematic testing of the effects of culture medium components on histone acetylation revealed that decreased sodium bicarbonate concentrations resulting in lowered extracellular and intracellular pH led to a rapid, marked reduction in total levels of histone H3 and H4 acetylation at multiple lysine residues. These pH-dependent changes were specific to histone acetylation, as histone methylation was unaffected and required ...
Protein acetylation affects gene expression, as well as other processes in cells, and it might be dependent on the availability of the metals. However, whether iron chelating compounds (siderophores) can have an effect on the acetylation process in plant roots is largely unknown. In the present study, western blotting and confocal microscopy was used to examine the degree of acetylation of histone H3 and alpha tubulin in Pinus sylvestris root cells in the presence of structurally different siderophores. The effect of metabolites that were produced by pathogenic and mycorrhizal fungi was also assessed. No effect was observed on histone acetylation. By contrast, the metabolites of the pathogenic fungus were able to decrease the level of microtubule acetylation, whereas treatment with iron-free ferrioxamine (DFO) was able to increase it. This latter was not observed when ferrioxamine-iron complexes were used. The pathogen metabolites induced important modifications of cytoskeleton organization.
Pathogen infection triggers complex molecular perturbations within host cells that results in either resistance or susceptibility. Protein acetylation is an emerging biochemical modification that appears to play central roles during host-pathogen interactions. To date, research in this area has focused on two main themes linking protein acetylation to plant immune signaling. Firstly, it has been established that proper gene expression during defense responses requires modulation of histone acetylation within target gene promoter regions. Second, some pathogens can deliver effector molecules that encode acetyltransferases directly within the host cell to modify acetylation of specific host proteins. Collectively these findings suggest that the acetylation level for a range of host proteins may be modulated to alter the outcome of pathogen infection. This review will focus on summarizing our current understanding of the roles of protein acetylation in plant defense and highlight the utility of proteomics
Posttranslational modification of proteins by acetylation and phosphorylation regulates most cellular processes in living organisms. Surprisingly, the evolutionary conservation of phosphorylated serine and threonine residues is only marginally higher than that of unmodified serines and threonines. With high-resolution mass spectrometry, we identified 1981 lysine acetylation sites in the proteome of Drosophila melanogaster. We used data sets of experimentally identified acetylation and phosphorylation sites in Drosophila and humans to analyze the evolutionary conservation of these modification sites between flies and humans. Site-level conservation analysis revealed that acetylation sites are highly conserved, significantly more so than phosphorylation sites. Furthermore, comparison of lysine conservation in Drosophila and humans with that in nematodes and zebrafish revealed that acetylated lysines were significantly more conserved than were nonacetylated lysines. Bioinformatics analysis using ...
The process of histone acetylation at lysine residues by histone acetyltransferase (HAT) is an important epigenetic marker and can be measured with the use of histone lysine acetylation antibodies . Acetylation of histones...
The distribution of acetylated isoforms of histone H4 along Chinese hamster chromosomes has been studied by immunostaining with antibodies recognizing H4 acetylated at defined lysines in its N-terminal domain. The heterochromatic long arm of the X chromosome in both female (CHO) and male (DON) cell lines is underacetylated at three out of four lysines (5, 8, and 12). In contrast, the level of acetylation at lysine 16, which is the first to be acetylated in mammals, was similar in X chromosomes and autosomes. Labeling of the cells with bromodeoxyuridine (BrdU) to mark late-replicating chromosome domains, followed by double immunostaining with antibodies to BrdU and acetylated H4, showed a close, though not perfect, correlation between late replication and low levels of H4 acetylation. The results show that levels of histone acetylation are associated with the replication timing of defined domains on both the X chromosome and autosomes, but the exceptions we observe suggest that this link is not absolute
Many studies have shown that SIRT3 deficiency results in increased mitochondrial acetylation and reduced activity of numerous mitochondrial enzymes (Newman et al, 2012). SIRT3 protein levels are increased upon fasting and calorie restriction (Shi et al, 2005; Palacios et al, 2009; Hirschey et al, 2010; Tao et al, 2010; Newman et al, 2012), and increased SIRT3 activity has been suggested to regulate metabolism under these conditions. However, with the exception of a single study (Fan et al, 2014), a regulatory axis between enzyme‐catalyzed acetylation and SIRT3‐mediated deacetylation has not been demonstrated. A hallmark of protein regulation by posttranslational modifications is site‐specific, enzyme‐catalyzed modification that mostly occurs in a conditional manner. However, there is little evidence of enzyme‐catalyzed, site‐specific acetylation in mitochondria, and several studies suggest that most mitochondrial acetylation occurs nonenzymatically (Wagner & Payne, 2013; Pougovkina ...
Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.. Read more → ...
Histone acetylation is a hallmark of chromatin that has an open structure that can be accessed by DNA and RNA polymerases as well as transcription factors, resulting in the activation of gene transcription (Filippakopoulos and Knapp, 2014). Correspondingly, histone methylation increases the basicity and hydrophobicity of histone tails and the affinity of certain proteins, such as transcription factors, toward DNA (Teperino et al., 2010), thus affecting the gene expression. In this database, we have collected 584 non-redundant protein data of 8 organisms including H. sapiens, M. musculus, R. norvegicus, D. melanogaster, C. elegans, A. thaliana, S. pombe and S. cerevisiae from the literature. The data are further classified into 15 families for histone acetylation writers, erasers and readers and 32 families for histone methylation writers, erasers and readers, respectively. WERAM 1.0 is a comprehensive Eukaryotic Writers, Erasers and Readers protein of Histone Acetylation and Methylation system ...
This study shows that Rb is a key regulator of differentiation and that acetylation is an important modification during this process. We have investigated the role of Rb acetylation in keratinocyte differentiation by mutating the major acetylation sites, lysines 873 and 874, to arginine and then determining the ability of the mutant to restore differentiation in Rb-knockdown keratinocytes. Mutation of the acetylation sites did not affect the ability of Rb to inhibit the proliferation, probably because of the fact that RbRR can interact with and inhibit E2F1 (Markham et al., 2006). This also suggests that inhibition of E2F family members is not sufficient to induce terminal differentiation, as has previously reported in the Saos-2 cell line (Sellers et al., 1998). However, unlike wild-type Rb, the acetylation mutant is unable to induce either early or late differentiation markers and, because Rb is acetylated relatively late during differentiation, this suggests that either the early events are ...
1. Acetylation Databases. (1) PhosphoSitePlus: (PSP) is a comprehensive, manually curated and interactive resource on post-translational modifications (PTM). PSP contains encompasses 130000 non-redundant modification sites, manily on phosphorylation, ubiquitinylation and acetylation (Hornbeck, et al., 2004). (2) g2pDB: A Database Mapping Protein Post-Translational Modifications to Genomic Coordinates. The original data comes mainly from published studies, many of which involve the investigation of post-translational modification acceptor site assignments, e.g., phosphorylation, ubiquitination, SUMOylation, acetylation, and N-linked glycosylation sites. (Keegan S, et al., 2016). (3) dbPTM 2.0: integrates experimentally verified PTMs from several databases, and to annotate the predicted PTMs on Swiss-Prot proteins , 2,071 acetylation sites were included while most of which were N-alpha-terminal ones (Lee TY, et al., 2006) . (4) HPRD release 9: HPRD currently contains information for 16,972 PTMs ...
TY - JOUR. T1 - Metabolic control of methylation and acetylation. AU - Su, Xiaoyang. AU - Wellen, Kathryn E.. AU - Rabinowitz, Joshua D.. PY - 2016/2/1. Y1 - 2016/2/1. N2 - Methylation and acetylation of DNA and histone proteins are the chemical basis for epigenetics. From bacteria to humans, methylation and acetylation are sensitive to cellular metabolic status. Modification rates depend on the availability of one-carbon and two-carbon substrates (S-adenosylmethionine, acetyl-CoA, and in bacteria also acetyl-phosphate). In addition, they are sensitive to demodification enzyme cofactors (α-ketoglutarate, NAD+) and structural analog metabolites that function as epigenetic enzyme inhibitors (e.g., S-adenosylhomocysteine, 2-hydroxyglutarate). Methylation and acetylation likely initially evolved to tailor protein activities in microbes to their metabolic milieu. While the extracellular environment of mammals is more tightly controlled, the combined impact of nutrient abundance and metabolic enzyme ...
|P>Eukaryotic transcription is a highly regulated process, and acetylation plays a major role in this regulation. Acetylation can occur on histones, DNA-binding TF (Transcription Factors), acetylases, nuclear import factors, non-nuclear proteins (Alpha-tubulin) and proteins that shuttle from the nucleus to [...]
Regulation of gene expression is mediated by several mechanisms including DNA methylation, ATP-dependent chromatin remodeling, and posttranslational modifications of histones. One of the major modifications of histones consists of the dynamic acetylation and deacetylation of ε-amino groups of lysine residues present in the tail of core histones.1 The enzymes responsible for this reversible acetylation/deacetylation process are histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively.2 While HATs act as transcriptional coactivators, HDACs are part of transcriptional corepressor complexes.
The two cotranslational processes, cleavage of N‐terminal methionine residues and N‐terminal acetylation, are by far the most common modifications, occurring on the vast majority of proteins. Proteins from prokaryotes, mitochondria and chloroplasts initiate with formylmethionine, whereas proteins from the cytosol of eukaryotes initiate with methionine. The formyl group is removed from prokaryotic proteins by a deformylase, resulting in methionine at the N‐termini. The methionine at the N‐termini is cleaved from nascent chains of most prokaryotic and eukaryotic proteins. N‐terminal acetylation occurs subsequently on certain of the proteins, either containing or lacking the methionine residue. This N‐terminal acetylation occurs on more than one‐half of eukaryotic proteins, but seldom on prokaryotic proteins (Driessen et al., 1985; Kendall et al., 1990).. Because the N‐terminal region of yeast iso‐1‐cytochrome c (iso‐1) is dispensable for biosynthesis, function and ...
TY - JOUR. T1 - The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. AU - Liu, Xin. AU - Wang, Ling. AU - Zhao, Kehao. AU - Thompson, Paul R.. AU - Hwang, Yousang. AU - Marmorstein, Ronen. AU - Cole, Philip A.. PY - 2008/2/14. Y1 - 2008/2/14. N2 - The transcriptional coactivator p300/CBP (CREBBP) is a histone acetyltransferase (HAT) that regulates gene expression by acetylating histones and other transcription factors. Dysregulation of p300/CBP HAT activity contributes to various diseases including cancer. Sequence alignments, enzymology experiments and inhibitor studies on p300/CBP have led to contradictory results about its catalytic mechanism and its structural relation to the Gcn5/PCAF and MYST HATs. Here we describe a high-resolution X-ray crystal structure of a semi-synthetic heterodimeric p300 HAT domain in complex with a bi-substrate inhibitor, Lys-CoA. This structure shows that p300/CBP is a distant cousin of other structurally characterized HATs, but ...
The 70kDa ribosomal protein S6 kinases (S6K1 and S6K2) play important roles in the regulation of protein synthesis, cell growth and survival. S6Ks are activated in response to mitogen stimulation and nutrient sufficiency by the phosphorylation of conserved serine and threonine residues. Here we show for the first time, that in addition to phosphorylation, S6Ks are also targeted by lysine acetylation. Following mitogen stimulation, S6Ks interact with the p300 and p300/CBP-associated factor (PCAF) acetyltransferases. S6Ks can be acetylated by p300 and PCAF in vitro and S6K acetylation is detected in cells expressing p300. Furthermore, it appears that the acetylation sites targeted by p300 lie within the divergent C-terminal regulatory domains of both S6K1 and S6K2. Acetylation of S6K1 and 2 is increased upon the inhibition of class I/II histone deacetylases (HDACs) by trichostatin-A, while the enhancement of S6K1 acetylation by nicotinamide suggests the additional involvement of sirtuin ...
Caltag Medsystems provide a range of kits to study histone acetylation and histone deacetylation which is involved the addition or removal of an acetyl group on lysine residues in the N-terminal tail and on the surface of the nucelosome core of histone proteins. Acetylated and deacetylated histones are considered epigenetic tags within chromatin by relaxing (euchromatin) or tightening (heterochromatin) chromatin structure, subsequently increasing or decreasing gene transcription levels. Kits are available for Histone Acetylation Quantification, Histone Acetyltransferase (HAT) Assays, and Histone Deacetylase (HDAC) Assays.
Nucleosome structure incorporated histone acetylation site prediction in arabidopsis thaliana. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
The epithelial to mesenchymal transition (EMT) enables epithelial cells with a migratory mesenchymal phenotype. It is activated in cancer cells and is involved in invasion, metastasis and stem-like properties. ZEB1, an E-box binding transcription factor, is a major suppressor of epithelial genes in lung cancer. In the present study, we show that in H358 non-small cell lung cancer cells, ZEB1 downregulates EpCAM (coding for an epithelial cell adhesion molecule), ESRP1 (epithelial splicing regulatory protein), ST14 (a membrane associated serine protease involved in HGF processing) and RAB25 (a small G-protein) by direct binding to these genes. Following ZEB1 induction, acetylation of histone H4 and histone H3 on lysine 9 (H3K9) and 27 (H3K27) was decreased on ZEB1 binding sites on these genes as demonstrated by chromatin immunoprecipitation. Of note, decreased H3K27 acetylation could be also detected by western blot and immunocytochemistry in ZEB1 induced cells. In lung cancers, H3K27 acetylation level
Jun dimerization protein-2 (JDP2) is a component of the AP-1 transcription factor that represses transactivation mediated by the Jun family of proteins. Here, we examine the functional mechanisms of JDP2 and show that it can inhibit p300-mediated acetylation of core histones in vitro and in vivo. Inhibition of histone acetylation requires the N-terminal 35 residues and the DNA-binding region of JDP2. In addition, we demonstrate that JDP2 has histone-chaperone activity in vitro. These results suggest that the sequence-specific DNA-binding protein JDP2 may control transcription via direct regulation of the modification of histones and the assembly of chromatin.
© 2014 The Authors. Gene transcription responds to stress and metabolic signals to optimize growth and survival. Histone H3 (H3) lysine 4 trimethylation (K4me3) facilitates state changes, but how levels are coordinated with the environment is unclear. Here, we show that isomerization of H3 at the alanine 15-proline 16 (A15-P16) peptide bond is influenced by lysine 14 (K14) and controls gene-specific K4me3 by balancing the actions of Jhd2, the K4me3 demethylase, and Spp1, a subunit of the Set1 K4 methyltransferase complex. Acetylation at K14 favors the A15-P16. trans conformation and reduces K4me3. Environmental stress-induced genes are most sensitive to the changes atK14 influencing H3 tail conformation and K4me3. By contrast, ribosomal protein genes maintain K4me3, required for their repression during stress, independently of Spp1, K14, and P16. Thus, the plasticity in control of K4me3, via signaling to K14 and isomerization at P16, informs distinct gene regulatory mechanisms and processes involving
Histone acetyltransferase (HATs) proteins are involved in histone acetylation, or the addition of an acetyl group to lysine residues in the N-terminal tail and on the surface of the nucelosome core of histone proteins. They...
On the other hand, if acetylation is reduced, 53BP1 outcompetes BRCA1 at a break and the non-homologous end-joining tool repairs the break. This mechanism can help explain resistance to a promising chemotherapy called PARP inhibition seen in patients and mouse models with BRCA1 mutations. Work from several other research teams surprisingly has shown that if neither BRCA nor 53BP1 are available, then the homologous recombination system goes into action even in the absence of BRCA1 and BRCA1 mutant cancer cells become resistant to PARP inhibitors. Because of this, Greenberg says, there are some possible applications for making PARP chemotherapy more sensitive: "If you could inhibit specific acetylation events, then a patients response to PARP inhibitors might be enhanced by hyperactivating 53BP1 binding to breaks in the context of BRCA1 deficient cancers. Whats more, measuring the levels of acetylation at H4 might predict how responsive an individual is to PARP inhibitors." "The story didnt ...
Sir3 N-terminal acetylation stabilizes the interaction of Sir3 BAH with the NCP(a) Superposition of the structures of the N-terminally acetylated (pink) and una
Reversible acetylation of histone and non-histone proteins is one of the most abundant post-translational modifications in eukaryotic cells. Protein acetylation and deacetylation are achieved by the antagonistic actions of two families of enzymes, histone acetyltransferases (HATs) and histone deacet …
Statement of Research Interests. My research interests focus on the regulation of gene transcription in eukaryotic organisms, and the consequences of this regulation for downstream developmental events. In particular, I am interested in how factors such as covalent modifications of histones, chromatin structure/architecture, and gene organization may act and interact to influence gene expression.. Impact of histone acetylation on plant development. Background on HATs and Histone Acetylation. One area of current research investigates the biological role of the histone acetyltransferase (HAT) enzyme GCN5 in developmental pathways in the model plant Arabidopsis thaliana. GCN5 can covalently modify histones (chromatin proteins) by catalyzing the addition of acetyl group to specific lysine residues. This modification is hypothesized to affect histone-DNA contacts or provide binding sites for other factors involved in regulating transcription (the histone code hypothesis), but the exact biochemical ...
We have also investigated the potential roles of several signaling pathways, which could mediate apoptosis in the NPC cells upon treatment by bortezomib/SAHA. Bortezomib was found to potentiate SAHAs acetylation of histones H3 and H4 in the NPC cells. Furthermore, the histone acetylation was ROS- and caspase-8-dependent as both NAC- and caspase-8-specific inhibitor, Z-IETD-FMK, could markedly reduce the acetylation of the histones. The results were similar to the induction of caspase-8-dependent histone acetylation by combination of HDAC and proteasome inhibitors in leukemic cells (21). One of the major effects mediated by histone hyperacetylation is upregulation of tumor suppressor genes (9). However, we did not find any upregulation of retinoblastoma (Rb) or p53 in the bortezomib/SAHA-treated NPC cells (refer to Supplementary Fig. S2A). The p53 expression was repressed by the combination treatment in HA cells, whereas such repression was not found in C666-1 cells. Because enhanced apoptosis ...
Figure 3. Genetically encoded N-epsilon lysine acetylation allows the high resolution X-ray structures of acetylated proteins and their complexes to be solved. The high resolution structure of acetyl lysine from acetylated cyclophilin (left) showing the experimental density. Right, Acetylated cyclophilin in complex with cyclosporine. Water molecules (blue spheres) that are ordered at the protein small molecule interface in the unacetylated complex) rearrange in the acetylated complex.. The acetylation of a cyclophilin at Lys125 was identified in a proteomics screen. We subsequently demonstrated that a substantial proportion of CYPA is acetylated in HeLa cells and human T cell lines, suggesting that the acetylated form of the protein is biologically relevant. To test this, recombinant CYPA bearing homogenous acetylation at Lys125 was prepared by overexpression in E. coli using an acetyllysyl-tRNA synthetase-tRNACUA pair, allowing detailed biophysical and enzymatic characterization of acetylated ...
p53 is the most well-characterized tumor suppressor, and its tumor-suppressive functions are dysregulated in more than 50% of human tumor tissues (29). The MDM2 oncogene is frequently amplified in many tumor tissues to functionally inactivate p53 (5), suggesting that inhibition of MDM2 activity might provide a robust method for cancer prevention. Previous studies have demonstrated that p300 cooperates with MDM2 and triggers p53 polyubiquitination as a ubiquitin E4 ligase (11, 30). Here, we propose a novel regulatory mechanism for p300 via acetylation-dependent control of the oncogenic function of MDM2. Specifically, p300 directly acetylates MDM2, a process that channels that E3 ligase activity away from MDM2 autoubiquitination to concentrate on promoting p53 ubiquitination, in part because of acetylation-induced alteration of intramolecular interaction of MDM2. Thus, p300 may regulate p53 ubiquitination through multiple regulatory mechanisms.. Furthermore, we identified that acetylation of MDM2 ...
BioAssay record AID 632979 submitted by ChEMBL: Inhibition of HDAC4 in human HL60 cells assessed as increase in histone H4 acetylation at 1 ug/ml after 24 hrs by Western blot analysis.
Reversible acetylation of histone and nonhistone proteins plays pivotal role in cellular homeostasis. Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, neurodegenaration, asthma, diabetes, AIDS, and cardiac hypertrophy. We describe the synthesis and characterization of a set of p300-HAT-specific small-molecule inhibitors from a natural nonspecific HAT inhibitor, garcinol, which is highly toxic to cells. We show that the specific inhibitor selectively represses the p300-mediated acetylation of p53 in vivo. Furthermore, inhibition of p300-HAT down regulates several genes but significantly a few important genes are also upregulated. Remarkably, these inhibitors were found to be nontoxic to T cells, inhibit histone acetylation of HIV infected cells, and consequently inhibit the multiplication of HIV.. ...
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Histone deacetylation and rDNA silencing.Transcriptionally silenced regions of eukaryotic genomes are generally hypoacetylated. In S. cerevisiae, the HM loci and telomeres are hypoacetylated on histones H3 and H4, with an acetylation pattern similar to that in higher eukaryotes (10). The yeast RPD3 gene product is the proposed catalytic component of a large multiprotein histone deacetylase complex (HDB) which acts in targeted transcriptional repression (40, 64). Sin3p, another subunit of HDB, acts to target the complex to specific Pol II promoters through association with specific DNA binding proteins (41). Sap30p is also a member of this complex (84). Paradoxically,rpd3 and sin3 mutations increase silencing atHM loci (77), telomeres (23, 64), and the rDNA (this study). Similarly, Drosophila TPE is enhanced by null mutations of its RPD3 homolog (23). In another study, sap30 mutants strengthened all types of silencing in yeast, including the rDNA (37). These findings were completely consistent ...
Histones are proteins in close contact with the DNA in the nucleus of a cell. They function to maintain the organization of DNA, and recent studies have shown that histones regulate the expression of genes. Histones can be modified by biochemical processes such as addition or removal of acetyl groups, known as acetylation and deacetylation. Such modifications have been shown to control genetic mechanisms important for memory storage in brain cells.. Ottavio Arancio, M.D. and colleagues studied mice that had been genetically altered to exhibit Alzheimer-like pathology. They found that long-term potentiation-a cellular model of memory formation in the brain-was reduced by drugs that prevent deacetylation of histones. Furthermore, acetylation of histones in these animals was greatly reduced after a behavioral training session in comparison to normal mice. They have proposed to extend these studies to examine whether impairments in histone acetylation or deacetylation are involved in the memory ...
To determine whether PKM2 K62 and K305 are direct SIRT2 deacetylation targets, we generated a series of PKM2 K62 and K305 mutants, including Flag-PKM2, Flag-PKM2K62R, Flag-PKM2K305R, and Flag-PKM2K62R/K305R. In these mutants, the substitution of a lysine with an arginine mimics constitutive deacetylation (9). These vectors were subsequently transfected into HEK-293T cells, and an in vitro deacetylation assay was performed. These results showed that PKM2−K305R and PKM2−K62/K305R exhibited lower acetylation levels as compared with PKM2-K62R (Fig. 3D, lanes 3 and 4 vs. lane 2), suggesting that lysine 305, but not 62, is deacetylated by SIRT2. Thus, when K305 is mutated, only K62 can be acetylated, and as such, the greater acetylation in the presence of K62R means that K305 was the primary contributor to the acetylation, as has been shown by other (30), whereas the lower acetylation in the presence of K305R means that K62 was not acetylated.. A tissue culture deacetylation assay was performed ...
TRIP-Brs are a recently discovered set of proteins whose functions remain poorly characterized. Here we report the identification of TRIP-Br3 as a member of the TRIP-Br family along with evidence showing that TRIP-Brs interact with bromodomain-containing transcriptional cofactors PCAF, STAF65γ, and KAP1. PCAF, a histone acetyltransferase; STAF65γ, a protein associated with histone acetylation activity; and KAP1, a corepressor, influence the transcriptional activity of TRIP-Brs differentially. Finally, while all three TRIP-Brs are localized to the nucleus, TRIP-Br2 and TRIP-Br3 are also present in the cytoplasm through interaction with CRM1. Our results suggest that different TRIP-Brs function by interacting with a wide variety of bromodomain-containing transcriptional regulators in different subcellular locales ...
Histone acetylation plays a key role in the regulation of eukaryotic gene expression. Histone acetylation and deacetylation are catalyzed by multisubunit complexes. The protein encoded by this gene is a component of the histone deacetylase complex, which includes SIN3, SAP30, HDAC1, HDAC2, RbAp46, RbAp48, and other polypeptides. This protein directly interacts with SIN3 and enhances SIN3-mediated transcriptional repression when tethered to the promoter. A pseudogene has been identified on chromosome 2. [provided by RefSeq, Dec 2008] ...
Histone deacetylase (HDAC) inhibitors are undergoing clinical trials as anticancer agents, but some exhibit resistance mechanisms linked to anti-apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family members might offer an improved therapeutic approach. We show here that a novel seleno-α-keto acid triggers global histone acetylation in human colon cancer cells and activates apoptosis in a p21-independent manner. Profiling of multiple survival factors identified a critical role for the BH3-only member Bcl-2-modifying factor (Bmf). On the corresponding BMF gene promoter, loss of HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein 3 (Sp3) transcription factor exchange and recruitment of p300. Treatment with a p300 inhibitor or transient overexpression of exogenous HDAC8 interfered with BMF induction, whereas RNAi-mediated silencing of STAT3 activated the target gene. This is the first report to
Specific genes that affect neuronal plasticity are crucial for long-term memory (Kandel et al., 2014). However, the molecules translated by these genes last only from several hours to several days, which may not maintain sufficient protein levels for long-term memory. In recent studies, epigenetics has been demonstrated to be the basis for the sustained regulation of gene transcription (Woldemichael et al., 2014). Specifically, histone acetylation has been thoroughly investigated in many mental diseases in recent years. Acetylation may occur in specific sites in histones and is regulated by two classes of enzymes, including histone acetyltransferase (HAT) and histone deacetylase (HDAC) (Szyf, 2014). The deacetylation of histones is induced by HDACs to ensure that DNA is tightly associated with histones and chromatin is "closed" for transcription (Narlikar et al., 2002; Penney and Tsai, 2014).. It has been reported that the nonspecific inhibitors of HDACs may significantly improve the performance ...
XRCC4-like factor (XLF) is the most recently discovered core member of the nonhomologous end joining (NHEJ) machinery. XLF enhances ligation of DNA ends by DNA ligase IV (LIG4) and functionally interacts with KU70. Previous results showed that some polymorphic changes in LIG4 impact on the efficiency of double strand breaks (DSBs) repair. A random Caucasian population sample was screened for XLF polymorphic mutations with similar functional impact. This analysis identified two novel noncoding single nucleotide polymorphisms (SNPs). To address the regulation of XLF and KU70, the acetylation status of both proteins were analysed. It has been found that XLF undergoes acetylation both in vitro and in vivo and the acetylation sites were mapped in vitro by mass spectrometry. Preliminary analysis has indicated that XLF deacetylation might be histone-deacetylase (HDAC3) dependent. For KU70, it has been found that lysine residues K317, K331 and K338 are critical for NHEJ. Cells overexpressing ...
View Notes - S10GenQuiz3Key from BIOL 283 at UMass (Amherst). A1. Youve isolated a mutant cell line that contains histones resistant to acetylation. What phenotype do you predict for this mutant? a.
There are comments on PubPeer for publication: Acetylation of RTN-1C regulates the induction of ER stress by the inhibition of HDAC activity in neuroectodermal tumors (2009)
Development of drugs that target epigenetic signaling mechanisms is a new and exciting strategy for the treatment of cancer. Epigenetic processes including chemical modifications to DNA and also to the histone proteins that package the DNA in chromatin play a central role in gene expression and regulation. One of the most frequently occurring modifications is the acetylation of lysine residues (Kac) and deregulation of this process has been associated with many common diseases, such as cancer, diabetes, obesity and Alzheimers disease. Historically, most therapeutic development has focused on the group of enzymes that "write" and "erase" acetylation marks on histones. But more recently, epigenetic "reader" proteins that sense the presence of these epigenetic marks are also being explored as novel therapeutic targets ...
Component of the HBO1 complex which has a histone H4-specific acetyltransferase activity, a reduced activity toward histone H3 and is responsible for the bulk of histone H4 acetylation in vivo. Transcriptional coactivator, it may also promote acetylation of nucleosomal histone H4 by KAT5. Promotes apoptosis. May act as a renal tumor suppressor. Negatively regulates canonical Wnt signaling; at least in part, cooperates with NPHP4 in this function (By similarity).
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We analyzed transcriptome changes in the athd1-t1 line in leaves and flower buds, two important developmental stages. In each comparison, we performed four dye-swap experiments using two biological replicates (supplementary Figure 1 and supplementary Table 1 at http://www.genetics.org/supplemental/). The data were analyzed using a linear model and the results were adjusted for multiple comparisons (Lee et al. 2004) to test the null hypothesis of no differential gene expression between the wild type (Ws) and athd1-t1. The data were analyzed using two versions of the same statistical test (i.e., t-test). The first analysis was based on a t-test using a common variance assumption for all genes, while the second analysis acknowledged the per-gene variances for individual genes via the biological replicates. The genes found to be statistically significant (α = 0.05) under per-gene variances included those that had relatively small fold changes but that may be biologically relevant (Lee et al. 2004). ...
Video created by Université de Melbourne for the course Le contrôle épigénétique de lexpression des gènes. Well discuss the molecular mechanisms for regulating gene expression in some detail, from how the DNA is packaged at a local level, ...
Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. Several lines of evidence also link HDACs to cancer. HDAC i...
CNS-22 was previously identified as an important cis-regulatory element hypothesized to have a central role in epigenetic remodeling of the Ifng locus during lineage-specific Th1, Tc1 and NK cell differentiation [13], [18]. In the current study, CNS-22-deficient mice were generated to enable study of the consequences of deletion of this element for epigenetic remodeling of the endogenous Ifng locus. Here we identify CNS-22 as critical element for early remodeling of the Ifng locus in naïve T cells and establish its importance as an enhancer for optimal Ifng transcription in Th1, Tc1 and NK cells. However, we find that the epigenetic consequences of the deletion of CNS-22 during lineage specification are limited to circumscribed effects on critical upstream regulatory elements surrounding CNS-22, such that remodeling of regulatory elements downstream of the Ifng gene occurs largely independently of CNS-22 in Th1 or Tc1 cells. Unexpectedly, fine mapping of the epigenetic consequences of CNS-22 ...