Journal articles on the topic 'Histone acetylation'
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1
Chicoine, L. G., R. Richman, R. G. Cook, M. A. Gorovsky, and C. D. Allis. "A single histone acetyltransferase from Tetrahymena macronuclei catalyzes deposition-related acetylation of free histones and transcription-related acetylation of nucleosomal histones." Journal of Cell Biology 105, no. 1 (July 1, 1987): 127–35. http://dx.doi.org/10.1083/jcb.105.1.127.
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A salt-extracted histone acetyltransferase activity from Tetrahymena macronuclei acetylates mostly histone H3 and H4 when free histones are used as substrate. Free histone H4 is acetylated first at position 11 (monoacetylated) or positions 11 and 4 (diacetylated). This activity strongly resembles in vivo, deposition-related acetylation of newly synthesized histones. When acetylase-free mononucleosomes are used as substrate, all four core histones are acetylated by the same extract, and H4 is acetylated first at position 7 (monoacetylated) or positions 7 and 4 (diacetylated). In this respect, the activity of the extract is indistinguishable from postsynthetic, transcription-related histone acetylation that occurs in vivo or in isolated nuclei. Heat inactivation curves with both substrates are indistinguishable, and free histones compete with chromatin for limiting amounts of enzyme activity. These results argue strongly that two distinct, biologically important histone acetylations, one deposition related and one transcription related, are carried out by a single acetyltransferase.
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Cuevas-Bennett, Christian, and Thomas Shenk. "Dynamic Histone H3 Acetylation and Methylation at Human Cytomegalovirus Promoters during Replication in Fibroblasts." Journal of Virology 82, no. 19 (July 23, 2008): 9525–36. http://dx.doi.org/10.1128/jvi.00946-08.
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ABSTRACT Human cytomegalovirus DNA is packaged in virions without histones but associates with histones upon reaching the nucleus of an infected cell. Since transcription is modulated by the interplay of histone modifications, we used chromatin immunoprecipitation to detect acetylation and methylation of histone H3 at viral promoters at different times during the viral replication cycle. Histone H3 at immediate-early promoters is acetylated at the start of infection, while it is initially methylated at early and late promoters. Acetylation at immediate-early promoters is dynamic, with a high level of activating modifications at 3 and 6 h postinfection (hpi), followed by a marked reduction at 12 hpi. All viral promoters, as well as nonpromoter regions, are modified with activating acetylations at 24 to 72 hpi. The transient reduction in histone H3 acetylation at the major immediate-early promoter depends on the cis-repressive sequence to which the UL122-coded IE2 protein binds. A mutant virus lacking this element exhibited decreased IE2 binding at the major immediate-early promoter and failed to show reduced acetylation of histone H3 residing at this promoter at 12 hpi. Our results demonstrate that cytomegalovirus chromatin undergoes dynamic, promoter-specific histone modifications early in the infectious cycle, after which the entire chromosome becomes highly acetylated.
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Legartová, Soňa, Stanislav Kozubek, Michal Franek, Zbyněk Zdráhal, Gabriela Lochmanová, Nadine Martinet, and Eva Bártová. "Cell differentiation along multiple pathways accompanied by changes in histone acetylation status." Biochemistry and Cell Biology 92, no. 2 (April 2014): 85–93. http://dx.doi.org/10.1139/bcb-2013-0082.
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Post-translational modification of histones is fundamental to the regulation of basic nuclear processes and subsequent cellular events, including differentiation. In this study, we analyzed acetylated forms of histones H2A, H2B, and H4 during induced differentiation in mouse (mESCs) and human (hESCs) embryonic stem cells and during induced enterocytic differentiation of colon cancer cells in vitro. Endoderm-like differentiation of mESCs induced by retinoic acid and enterocytic differentiation induced by histone deacetylase inhibitor sodium butyrate were accompanied by increased mono-, di-, and tri-acetylation of histone H2B and a pronounced increase in di- and tri-acetylation of histone H4. In enterocytes, mono-acetylation of histone H2A also increased and tetra-acetylation of histone H4 appeared only after induction of this differentiation pathway. During differentiation of hESCs, we observed increased mono-acetylation and decreased tri-acetylation of H2B. Mono-, di-, and tri-acetylation of H4 were reduced, manifested by a significant increase in nonacetylated H4 histones. Levels of acetylated histones increased during induced differentiation in mESCs and during histone deacetylase (HDAC) inhibitor-induced enterocytic differentiation, whereas differentiation of human ESCs was associated with reduced acetylation of histones H2B and H4.
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Kring, Friedhelm, and Peter Böger. "Histone Acetylation is not Affected by Chloroacetamides in vitro." Zeitschrift für Naturforschung C 49, no. 5-6 (June 1, 1994): 309–11. http://dx.doi.org/10.1515/znc-1994-5-605.
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Abstract The effects of chloroacetamides on the acetylation of histone protein in maize (Zea mays) were studied in an in vitro assay. Neither alachlor nor metazachlor showed any influence on both of the investigated acetylating enzymes, the nuclear histone acetyltransferase A and the cytoplasmic histone acetyltransferase B. Furthermore, an effect of these herbicides on deacetylation of histones could be excluded.
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CraneRobinson, Colyn. "Playing tag: Histone acetylation." Biochemist 29, no. 4 (August 1, 2007): 9–13. http://dx.doi.org/10.1042/bio02904009.
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Acetylation of the e-amino group of specific lysine residues of core histones – principally but not exclusively in their unstructured N-terminal tails – is a key biochemical modification for establishing the transcriptional competence of genes bound by such histones. High resolution mapping of acetylated core histones by chromatin IPs (ChIPs) has shown them to be preferentially located at the promoters and enhancers of active genes rather than throughout the transcribed regions. Particular distributions of acetylated lysines are part of the nucleosomal ‘histone code’ that defines and to a considerable extent determines the functional status of the local chromatin. HHe istone acetylation is deposited and removed by numerous histone acetyltransferases (HATs) and deacetylases (HDACs) and acetyl-lysines are recognised (i.e. the histone code is ‘read’) by bromodomain-containing proteins.
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Demyanenko, Svetlana, and Svetlana Sharifulina. "The Role of Post-Translational Acetylation and Deacetylation of Signaling Proteins and Transcription Factors after Cerebral Ischemia: Facts and Hypotheses." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7947. http://dx.doi.org/10.3390/ijms22157947.
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Histone deacetylase (HDAC) and histone acetyltransferase (HAT) regulate transcription and the most important functions of cells by acetylating/deacetylating histones and non-histone proteins. These proteins are involved in cell survival and death, replication, DNA repair, the cell cycle, and cell responses to stress and aging. HDAC/HAT balance in cells affects gene expression and cell signaling. There are very few studies on the effects of stroke on non-histone protein acetylation/deacetylation in brain cells. HDAC inhibitors have been shown to be effective in protecting the brain from ischemic damage. However, the role of different HDAC isoforms in the survival and death of brain cells after stroke is still controversial. HAT/HDAC activity depends on the acetylation site and the acetylation/deacetylation of the main proteins (c-Myc, E2F1, p53, ERK1/2, Akt) considered in this review, that are involved in the regulation of cell fate decisions. Our review aims to analyze the possible role of the acetylation/deacetylation of transcription factors and signaling proteins involved in the regulation of survival and death in cerebral ischemia.
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Waterborg, Jakob H., and Tamás Kapros. "Kinetic analysis of histone acetylation turnover and Trichostatin A induced hyper- and hypoacetylation in alfalfa." Biochemistry and Cell Biology 80, no. 3 (June 1, 2002): 279–93. http://dx.doi.org/10.1139/o02-021.
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Dynamic histone acetylation is a characteristic of chromatin transcription. The first estimates for the rate of acetylation turnover of plants are reported, measured in alfalfa cells by pulse, pulse-chase, and steady-state acetylation labeling. Acetylation turnover half-lives of about 0.5 h were observed by all methods used for histones H3, H4, and H2B. This is consistent with the rate at which changes in gene expression occur in plants. Treatment with histone deacetylase inhibitor Trichostatin A (TSA) induced hyperacetylation at a similar rate. Replacement histone variant H3.2, preferentially localized in highly acetylated chromatin, displayed faster acetyl turnover. Histone H2A with a low level of acetylation was not subject to rapid turnover or hyperacetylation. Patterns of acetate labeling revealed fundamental differences between histone H3 versus histones H4 and H2B. In H3, acetylation of all molecules, limited by lysine methylation, had similar rates, independent of the level of lysine acetylation. Acetylation of histones H4 and H2B was seen in only a fraction of all molecules and involved multiacetylation. Acetylation turnover rates increased from mono- to penta- and hexaacetylated forms, respectively. TSA was an effective inhibitor of alfalfa histone deacetylases in vivo and caused a doubling in steady-state acetylation levels by 46 h after addition. However, hyperacetylation was transient due to loss of TSA inhibition. TSA-induced overexpression of cellular deacetylase activity produced hypoacetylation by 18 h treatment with enhanced acetate turnover labeling of alfalfa histones. Thus, application of TSA to change gene expression in vivo in plants may have unexpected consequences.
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Deckert, Jutta, and Kevin Struhl. "Histone Acetylation at Promoters Is Differentially Affected by Specific Activators and Repressors." Molecular and Cellular Biology 21, no. 8 (April 15, 2001): 2726–35. http://dx.doi.org/10.1128/mcb.21.8.2726-2735.2001.
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ABSTRACT We analyzed the relationship between histone acetylation and transcriptional regulation at 40 Saccharomyces cerevisiaepromoters that respond to specific activators and repressors. In accord with the general correlation between histone acetylation and transcriptional activity, Gcn4 and the general stress activators (Msn2 and Msn4) cause increased acetylation of histones H3 and H4. Surprisingly, Gal4-dependent activation is associated with a dramatic decrease in histone H4 acetylation, whereas acetylation of histone H3 is unaffected. A specific decrease in H4 acetylation is also observed, to a lesser extent, at promoters activated by Hap4, Adr1, Met4, and Ace1. Activation by heat shock factor has multiple effects; H4 acetylation increases at some promoters, whereas other promoters show an apparent decrease in H3 and H4 acetylation that probably reflects nucleosome loss or gross alteration of chromatin structure. Repression by targeted recruitment of the Sin3-Rpd3 histone deacetylase is associated with decreased H3 and H4 acetylation, whereas repression by Cyc8-Tup1 is associated with decreased H3 acetylation but variable effects on H4 acetylation; this suggests that Cyc8-Tup1 uses multiple mechanisms to reduce histone acetylation at promoters. Thus, individual activators confer distinct patterns of histone acetylation on target promoters, and transcriptional activation is not necessarily associated with increased acetylation. We speculate that the activator-specific decrease in histone H4 acetylation is due to blocking the access or function of an H4-specific histone acetylase such as Esa1.
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Ito, Takashi, Tsuyoshi Ikehara, Takeya Nakagawa, W. Lee Kraus, and Masami Muramatsu. "p300-Mediated acetylation facilitates the transfer of histone H2A–H2B dimers from nucleosomes to a histone chaperone." Genes & Development 14, no. 15 (August 1, 2000): 1899–907. http://dx.doi.org/10.1101/gad.14.15.1899.
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We have used a purified recombinant chromatin assembly system, including ACF (Acf-1 + ISWI) and NAP-1, to examine the role of histone acetylation in ATP-dependent chromatin remodeling. The binding of a transcriptional activator (Gal4–VP16) to chromatin assembled using this recombinant assembly system dramatically enhances the acetylation of nucleosomal core histones by the histone acetyltransferase p300. This effect requires both the presence of Gal4-binding sites in the template and the VP16-activation domain. Order-of-addition experiments indicate that prior activator-meditated, ATP-dependent chromatin remodeling by ACF is required for the acetylation of nucleosomal histones by p300. Thus, chromatin remodeling, which requires a transcriptional activator, ACF and ATP, is an early step in the transcriptional process that regulates subsequent core histone acetylation. Glycerol gradient sedimentation and immunoprecipitation assays demonstrate that the acetylation of histones by p300 facilitates the transfer of H2A–H2B from nucleosomes to NAP-1. The results from these biochemical experiments suggest that (1) transcriptional activators (e.g., Gal4–VP16) and chromatin remodeling complexes (e.g., ACF) induce chromatin remodeling in the absence of histone acetylation; (2) transcriptional activators recruit histone acetyltransferases (e.g., p300) to promoters after chromatin remodeling has occurred; and (3) histone acetylation is important for a step subsequent to chromatin remodeling and results in the transfer of histone H2A–H2B dimers from nucleosomes to a histone chaperone such as NAP-1. Our results indicate a precise role for histone acetylation, namely to alter the structure of nucleosomes (e.g., facilitate the loss of H2A–H2B dimers) that have been remodeled previously by the action of ATP-dependent chromatin remodeling complexes. Thus, transcription from chromatin templates is ordered and sequential, with precise timing and roles for ATP-dependent chromatin remodeling, subsequent histone acetylation, and alterations in nucleosome structure.
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Herrera, Julio E., Katherine L. West, R. Louis Schiltz, Yoshihiro Nakatani, and Michael Bustin. "Histone H1 Is a Specific Repressor of Core Histone Acetylation in Chromatin." Molecular and Cellular Biology 20, no. 2 (January 15, 2000): 523–29. http://dx.doi.org/10.1128/mcb.20.2.523-529.2000.
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ABSTRACT Although a link between histone acetylation and transcription has been established, it is not clear how acetylases function in the nucleus of the cell and how they access their targets in a chromatin fiber containing H1 and folded into a highly condensed structure. Here we show that the histone acetyltransferase (HAT) p300/CBP-associated factor (PCAF), either alone or in a nuclear complex, can readily acetylate oligonucleosomal substrates. The linker histones, H1 and H5, specifically inhibit the acetylation of mono- and oligonucleosomes and not that of free histones or histone-DNA mixtures. We demonstrate that the inhibition is due mainly to steric hindrance of H3 by the tails of linker histones and not to condensation of the chromatin fiber. Cellular PCAF, which is complexed with accessory proteins in a multiprotein complex, can overcome the linker histone repression. We suggest that linker histones hinder access of PCAF, and perhaps other HATs, to their target acetylation sites and that perturbation of the linker histone organization in chromatin is a prerequisite for efficient acetylation of the histone tails in nucleosomes.
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Jiang, Lihua, Jonell N. Smith, Shannon L. Anderson, Ping Ma, Craig A. Mizzen, and Neil L. Kelleher. "Global Assessment of Combinatorial Post-translational Modification of Core Histones in Yeast Using Contemporary Mass Spectrometry." Journal of Biological Chemistry 282, no. 38 (July 24, 2007): 27923–34. http://dx.doi.org/10.1074/jbc.m704194200.
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A global view of all core histones in yeast is provided by tandem mass spectrometry of intact histones H2A, H2B, H4, and H3. This allowed detailed characterization of >50 distinct histone forms and their semiquantitative assessment in the deletion mutants gcn5Δ, spt7Δ, ahc1Δ, and rtg2Δ, affecting the chromatin remodeling complexes SAGA, SLIK, and ADA. The “top down” mass spectrometry approach detected dramatic decreases in acetylation on H3 and H2B in gcn5Δ cells versus wild type. For H3 in wild type cells, tandem mass spectrometry revealed a direct correlation between increases of Lys4 trimethylation and the 0, 1, 2, and 3 acetylation states of histone H3. The results show a wide swing from 10 to 80% Lys4 trimethylation levels on those H3 tails harboring 0 or 3 acetylations, respectively. Reciprocity between these chromatin marks was apparent, since gcn5Δ cells showed a 30% decrease in trimethylation levels on Lys4 in addition to a decrease of acetylation levels on H3 in bulk chromatin. Deletion of Set1, the Lys4 methyltransferase, was associated with the linked disappearance of both Lys4 methylation and Lys14 and Lys18 or Lys23 acetylation on H3. In sum, we have defined the “basis set” of histone forms present in yeast chromatin using a current mass spectrometric approach that both quickly profiles global changes and directly probes the connectivity of modifications on the same histone.
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Adimulam, Theolan, Thilona Arumugam, Ashmika Foolchand, Terisha Ghazi, and Anil A. Chuturgoon. "The Effect of Organoselenium Compounds on Histone Deacetylase Inhibition and Their Potential for Cancer Therapy." International Journal of Molecular Sciences 22, no. 23 (November 30, 2021): 12952. http://dx.doi.org/10.3390/ijms222312952.
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Genetic and epigenetic changes alter gene expression, contributing to cancer. Epigenetic changes in cancer arise from alterations in DNA and histone modifications that lead to tumour suppressor gene silencing and the activation of oncogenes. The acetylation status of histones and non-histone proteins are determined by the histone deacetylases and histone acetyltransferases that control gene transcription. Organoselenium compounds have become promising contenders in cancer therapeutics. Apart from their anti-oxidative effects, several natural and synthetic organoselenium compounds and metabolites act as histone deacetylase inhibitors, which influence the acetylation status of histones and non-histone proteins, altering gene transcription. This review aims to summarise the effect of natural and synthetic organoselenium compounds on histone and non-histone protein acetylation/deacetylation in cancer therapy.
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Endo, Tsutomu, Aoi Imai, Takuma Shimaoka, Kiyoshi Kano, and Kunihiko Naito. "Histone exchange activity and its correlation with histone acetylation status in porcine oocytes." REPRODUCTION 141, no. 4 (April 2011): 397–405. http://dx.doi.org/10.1530/rep-10-0164.
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In mammalian oocytes, histone H3 and histone H4 (H4) in the chromatin are highly acetylated at the germinal vesicle (GV) stage, and become globally deacetylated after GV breakdown (GVBD). Although nuclear core histones can be exchanged by cytoplasmic free histones in somatic cells, it remains unknown whether this is also the case in mammalian oocytes. In this study, we examined the histone exchange activity in maturing porcine oocytes before and after GVBD, and investigated the correlations between this activity and both the acetylation profile of the H4 N-terminal tail and the global histone acetylation level in the chromatin. We injected Flag-tagged H4 (H4-Flag) mRNA into GV oocytes, and found that the Flag signal was localized to the chromatin. We next injected mRNAs of mutated H4-Flag, which lack all acetylation sites and the whole N-terminal tail, and found that the H4 N-terminal tail and its modification were not necessary for histone incorporation into chromatin. Despite the lack of acetylation sites, the mutated H4-Flag mRNA injection did not decrease the acetylation level on the chromatin, indicating that the histone exchange occurs partially in the GV chromatin. In contrast to GV oocytes, the Flag signal was not detected on the chromatin after the injection of H4-Flag protein into the second meiotic metaphase oocytes. These results suggest that histone exchange activity changes during meiotic maturation in porcine oocytes, and that the acetylation profile of the H4 N-terminal tail has no effect on histone incorporation into chromatin and does not affect the global level of histone acetylation in it.
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Hendzel, M. J., and J. R. Davie. "Dynamically acetylated histones of chicken erythrocytes are selectively methylated." Biochemical Journal 273, no. 3 (February 1, 1991): 753–58. http://dx.doi.org/10.1042/bj2730753.
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The relationship between histone acetylation and methylation in chicken immature erythrocytes was investigated. Previous studies have shown that transcriptionally active/competent gene-enriched chromatin fragments are enriched in newly methylated histones H3 and H4. Moreover, newly methylated histone H4 is hyperacetylated. Here, we show that dynamically acetylated histone H4 is selectively engaged in ongoing methylation. While sodium butyrate (an inhibitor of histone deacetylase) does not inhibit ongoing histone methylation, it does affect the acetylation state of newly methylated histone H4 when chicken immature erythrocytes are incubated in its presence or absence. Only one rate of acetylation of labelled newly methylated unacetylated histone H4 with a t1/2 of 8 min is observed. Previous studies have shown that the solubility of transcriptionally active/competent gene chromatin fragments in 0.15 M-NaCl is dependent upon the level of acetylated histone species, with induction of hyperacetylation increasing the solubility of this gene chromatin. Here, we show that the low salt solubility of chromatin fragments associated with newly methylated histones H3 and H4 is also dependent upon the level of acetylated histones. These results provide further support for the hypothesis that histones participating in ongoing methylation are associated with transcriptionally active/competent chromatin and suggest that the processes of histone H4 methylation and dynamic acetylation are partially coupled in terminally differentiated erythrocytes.
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Choi, Jennifer K., and LeAnn J. Howe. "Histone acetylation: truth of consequences?This 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." Biochemistry and Cell Biology 87, no. 1 (February 2009): 139–50. http://dx.doi.org/10.1139/o08-112.
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Eukaryotic DNA is packaged into a nucleoprotein structure known as chromatin, which is comprised of DNA, histones, and nonhistone proteins. Chromatin structure is highly dynamic, and can shift from a transcriptionally inactive state to an active form in response to intra- and extracellular signals. A major factor in chromatin architecture is the covalent modification of histones through the addition of chemical moieties, such as acetyl, methyl, ubiquitin, and phosphate groups. The acetylation of the amino-terminal tails of histones is a process that is highly conserved in eukaryotes, and was one of the earliest histone modifications characterized. Since its identification in 1964, a large body of evidence has accumulated demonstrating that histone acetylation plays an important role in transcription. Despite our ever-growing understanding of the nuclear processes involved in nucleosome acetylation, however, the exact biochemical mechanisms underlying the downstream effects of histone acetylation have yet to be fully elucidated. To date, histone acetylation has been proposed to function in 2 nonmutually exclusive manners: by directly altering chromatin structure, and by acting as a molecular tag for the recruitment of chromatin-modifying complexes. Here, we discuss recent research focusing on these 2 potential roles of histone acetylation and clarify what we actually know about the function of this modification.
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Johnson, Kristen, Cristina Angelin-Duclos, Sinae Park, and Kathryn L. Calame. "Changes in Histone Acetylation Are Associated with Differences in Accessibility of VH Gene Segments to V-DJ Recombination during B-Cell Ontogeny and Development." Molecular and Cellular Biology 23, no. 7 (April 1, 2003): 2438–50. http://dx.doi.org/10.1128/mcb.23.7.2438-2450.2003.
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ABSTRACT Although V(D)J recombination is thought to be regulated by changes in the accessibility of chromatin to the recombinase machinery, the mechanisms responsible for establishing “open” chromatin are poorly understood. We performed a detailed study of the acetylation status of histones associated with 11 VH gene segments, their flanking regions, and various intergenic elements during B-cell development and ontogeny, when V(D)J recombination is highly regulated. Histone H4 shows higher and more-regulated acetylation than does histone H3 in the VH locus. In adult pro-B cells, VH gene segments are acetylated prior to V(D)J rearrangement, with higher acetylation associated with JH-distal VH gene segments. While large regions of the VH locus have similar patterns of histone acetylation, acetylation is narrowly confined to the gene segments, their flanking promoters, and recombinase signal sequence elements. Thus, histone acetylation in the VH locus is both locally and globally regulated. Increased histone acetylation accompanies preferential recombination of JH-proximal VH gene segments in early B-cell ontogeny, and decreased histone acetylation accompanies inhibition of V-DJ recombination in a transgenic model of immunoglobulin heavy-chain allelic exclusion. Thus, changes in histone acetylation appear to be important for both promotion and inhibition of V-DJ rearrangement during B-cell ontogeny and development.
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Swaminathan, V., A. Hari Kishore, K. K. Febitha, and Tapas K. Kundu. "Human Histone Chaperone Nucleophosmin Enhances Acetylation-Dependent Chromatin Transcription." Molecular and Cellular Biology 25, no. 17 (September 1, 2005): 7534–45. http://dx.doi.org/10.1128/mcb.25.17.7534-7545.2005.
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ABSTRACT Histone chaperones are a group of proteins that aid in the dynamic chromatin organization during different cellular processes. Here, we report that the human histone chaperone nucleophosmin interacts with the core histones H3, H2B, and H4 but that this histone interaction is not sufficient to confer the chaperone activity. Significantly, nucleophosmin enhances the acetylation-dependent chromatin transcription and it becomes acetylated both in vitro and in vivo. Acetylation of nucleophosmin and the core histones was found to be essential for the enhancement of chromatin transcription. The acetylated NPM1 not only shows an increased affinity toward acetylated histones but also shows enhanced histone transfer ability. Presumably, nucleophosmin disrupts the nucleosomal structure in an acetylation-dependent manner, resulting in the transcriptional activation. These results establish nucleophosmin (NPM1) as a human histone chaperone that becomes acetylated, resulting in the enhancement of chromatin transcription.
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Cote, Joy M., Yin-Ming Kuo, Ryan A. Henry, Hataichanok Scherman, Daniel D. Krzizike, and Andrew J. Andrews. "Two factor authentication: Asf1 mediates crosstalk between H3 K14 and K56 acetylation." Nucleic Acids Research 47, no. 14 (June 13, 2019): 7380–91. http://dx.doi.org/10.1093/nar/gkz508.
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Abstract The ability of histone chaperone Anti-silencing factor 1 (Asf1) to direct acetylation of lysine 56 of histone H3 (H3K56ac) represents an important regulatory step in genome replication and DNA repair. In Saccharomyces cerevisiae, Asf1 interacts functionally with a second chaperone, Vps75, and the lysine acetyltransferase (KAT) Rtt109. Both Asf1 and Vps75 can increase the specificity of histone acetylation by Rtt109, but neither alter selectivity. However, changes in acetylation selectivity have been observed in histones extracted from cells, which contain a plethora of post-translational modifications. In the present study, we use a series of singly acetylated histones to test the hypothesis that histone pre-acetylation and histone chaperones function together to drive preferential acetylation of H3K56. We show that pre-acetylated H3K14ac/H4 functions with Asf1 to drive specific acetylation of H3K56 by Rtt109–Vps75. Additionally, we identified an exosite containing an acidic patch in Asf1 and show that mutations to this region alter Asf1-mediated crosstalk that changes Rtt109–Vps75 selectivity. Our proposed mechanism suggests that Gcn5 acetylates H3K14, recruiting remodeler complexes, allowing for the Asf1-H3K14ac/H4 complex to be acetylated at H3K56 by Rtt109–Vps75. This mechanism explains the conflicting biochemical data and the genetic links between Rtt109, Vps75, Gcn5 and Asf1 in the acetylation of H3K56.
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Friis, R. Magnus N., and Michael C. Schultz. "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." Biochemistry and Cell Biology 87, no. 1 (February 2009): 107–16. http://dx.doi.org/10.1139/o08-097.
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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.
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Hamam, Hussein, Meraj Khan, and Nades Palaniyar. "Histone Acetylation Promotes Neutrophil Extracellular Trap Formation." Biomolecules 9, no. 1 (January 18, 2019): 32. http://dx.doi.org/10.3390/biom9010032.
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Neutrophils undergo a unique form of cell death to generate neutrophil extracellular traps (NETs). It is well established that citrullination of histones (e.g., CitH3) facilitates chromatin decondensation during NET formation (NETosis), particularly during calcium-induced NETosis that is independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activation. However, the importance of other forms of histone modifications in NETosis has not been established. We considered that acetylation of histones would also facilitate NETosis. To test this hypothesis, we induced NOX-dependent NETosis in human neutrophils with phorbol myristate acetate or lipopolysaccharide (from Escherichia coli 0128), and NOX-independent NETosis with calcium ionophores A23187 or ionomycin (from Streptomyces conglobatus) in the presence or absence of two pan histone deacetylase inhibitors (HDACis), belinostat and panobinostat (within their half maximal inhibitory concentration (IC50) range). The presence of these inhibitors increased histone acetylation (e.g., AcH4) in neutrophils. Histone acetylation was sufficient to cause a significant increase (~20%) in NETosis in resting neutrophils above baseline values. When acetylation was promoted during NOX-dependent or -independent NETosis, the degree of NETosis additively increased (~15–30%). Reactive oxygen species (ROS) production is essential for baseline NETosis (mediated either by NOX or mitochondria); however, HDACis did not promote ROS production. The chromatin decondensation step requires promoter melting and transcriptional firing in both types of NETosis; consistent with this point, suppression of transcription prevented the NETosis induced by the acetylation of histones. Collectively, this study establishes that histone acetylation (e.g., AcH4) promotes NETosis at baseline, and when induced by both NOX-dependent or -independent pathway agonists, in human neutrophils. Therefore, we propose that acetylation of histone is a key component of NETosis.
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Wang, Yonggang, Xiao Miao, Yucheng Liu, Fengsheng Li, Quan Liu, Jian Sun, and Lu Cai. "Dysregulation of Histone Acetyltransferases and Deacetylases in Cardiovascular Diseases." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/641979.
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Cardiovascular disease (CVD) remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors which contribute to CVD is required in order to develop more effective treatment options. Dysregulation of epigenetic posttranscriptional modifications of histones in chromatin is thought to be associated with the pathology of many disease models, including CVD. Histone acetyltransferases (HATs) and deacetylases (HDACs) are regulators of histone lysine acetylation. Recent studies have implicated a fundamental role of reversible protein acetylation in the regulation of CVDs such as hypertension, pulmonary hypertension, diabetic cardiomyopathy, coronary artery disease, arrhythmia, and heart failure. This reversible acetylation is governed by enzymes that HATs add or HDACs remove acetyl groups respectively. New evidence has revealed that histone acetylation regulators blunt cardiovascular and related disease states in certain cellular processes including myocyte hypertrophy, apoptosis, fibrosis, oxidative stress, and inflammation. The accumulating evidence of the detrimental role of histone acetylation in cardiac disease combined with the cardioprotective role of histone acetylation regulators suggests that the use of histone acetylation regulators may serve as a novel approach to treating the millions of patients afflicted by cardiac diseases worldwide.
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Bartl, S., J. Taplick, G. Lagger, H. Khier, K. Kuchler, and C. Seiser. "Identification of mouse histone deacetylase 1 as a growth factor-inducible gene." Molecular and Cellular Biology 17, no. 9 (September 1997): 5033–43. http://dx.doi.org/10.1128/mcb.17.9.5033.
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Reversible acetylation of core histones plays an important role in transcriptional regulation, cell cycle progression, and developmental events. The acetylation state of histones is controlled by the activities of acetylating and deacetylating enzymes. By using differential mRNA display, we have identified a mouse histone deacetylase gene, HD1, as an interleukin-2-inducible gene in murine T cells. Sequence alignments revealed that murine HD1 is highly homologous to the yeast RPD3 pleiotropic transcriptional regulator. Indirect immunofluorescence microscopy proved that mouse HD1 is a nuclear protein. When expressed in yeast, murine HD1 was also detected in the nucleus, although it failed to complement the rpd3delta deletion phenotype. HD1 mRNA expression was low in G0 mouse cells but increased when the cells crossed the G1/S boundary after growth stimulation. Immunoprecipitation experiments and functional in vitro assays showed that HD1 protein is associated with histone deacetylase activity. Both HD1 protein levels and total histone deacetylase activity increased upon interleukin-2 stimulation of resting B6.1 cells. When coexpressed with a luciferase reporter construct, HD1 acted as a negative regulator of the Rous sarcoma virus enhancer/promoter. HD1 overexpression in stably transfected Swiss 3T3 cells caused a severe delay during the G2/M phases of the cell cycle. Our results indicate that balanced histone acetylation/deacetylation is crucial for normal cell cycle progression of mammalian cells.
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Loyola, Alejandra, Gary LeRoy, Yuh-Hwa Wang, and Danny Reinberg. "Reconstitution of recombinant chromatin establishes a requirement for histone-tail modifications during chromatin assembly and transcription." Genes & Development 15, no. 21 (November 1, 2001): 2837–51. http://dx.doi.org/10.1101/gad.937401.
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The human ISWI-containing factor RSF (remodeling andspacing factor) was found to mediate nucleosome deposition and, in the presence of ATP, generate regularly spaced nucleosome arrays. Using this system, recombinant chromatin was reconstituted with bacterially produced histones. Acetylation of the histone tails was found to play an important role in establishing regularly spaced nucleosome arrays. Recombinant chromatin lacking histone acetylation was impaired in directing transcription. Histone-tail modifications were found to regulate transcription from the recombinant chromatin. Acetylation of the histone tails by p300 was found to increase transcription. Methylation of the histone H3 tail by Suv39H1 was found to repress transcription in an HP1-dependent manner. The effects of histone-tail modifications were observed in nuclear extracts. A highly reconstituted RNA polymerase II transcription system was refractory to the effect imposed by acetylation and methylation.
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Weiss, G., H. Talasz, and B. Puschendorf. "Possible role of histone acetylation and histone H1° replacement for the initiation of replication in regenerating rat liver." Biochemical Journal 280, no. 3 (December 15, 1991): 777–81. http://dx.doi.org/10.1042/bj2800777.
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The role of histone acetylation and DNA synthesis has been investigated extensively in the regenerating rat liver system in the presence and absence of the cyclophosphamide derivative mafosfamide. We demonstrate a mafosfamide-induced inhibition of maximum histone acetyltransferase activity followed by a second elevation of enzyme activity and an accompanying total suppression of DNA synthesis for 7-8 h. The maximum of histone acetyltransferase activity, in parallel with an elevated acetylation in vivo, the consecutive replacement of histone H1(0) amd initiation of replication occur sequentially in the presence and absence of mafosfamide, but with a temporary delay of 7-8 h. Our data indicate that modifications of histone acetyltransferase (EC 2.3.1.48) activity do not significantly influence the acetylation patterns of histones H3 and H4. The mafosfamide-induced change of histone acetyltransferase activity and acetylation in vivo, the shift of histone H1(0) exchange and the consecutive transition of initiation of replication suggest that these three events might be functionally related.
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Barnes, Claire E., David M. English, and Shaun M. Cowley. "Acetylation & Co: an expanding repertoire of histone acylations regulates chromatin and transcription." Essays in Biochemistry 63, no. 1 (April 2019): 97–107. http://dx.doi.org/10.1042/ebc20180061.
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Abstract Packaging the long and fragile genomes of eukaryotic species into nucleosomes is all well and good, but how do cells gain access to the DNA again after it has been bundled away? The solution, in every species from yeast to man, is to post-translationally modify histones, altering their chemical properties to either relax the chromatin, label it for remodelling or make it more compact still. Histones are subject to a myriad of modifications: acetylation, methylation, phosphorylation, ubiquitination etc. This review focuses on histone acylations, a diverse group of modifications which occur on the ε-amino group of Lysine residues and includes the well-characterised Lysine acetylation. Over the last 50 years, histone acetylation has been extensively characterised, with the discovery of histone acetyltransferases (HATs) and histone deacetylases (HDACs), and global mapping experiments, revealing an association of hyperacetylated histones with accessible, transcriptionally active chromatin. More recently, there has been an explosion in the number of unique short chain ‘acylations’ identified by MS, including: propionylation, butyrylation, crotonylation, succinylation, malonylation and 2-hydroxyisobutyrylation. These novel modifications add a range of chemical environments to histones, and similar to acetylation, appear to accumulate at transcriptional start sites and correlate with gene activity.
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Harb, Hani, Bilal Alashkar Alhamwe, Nathalie Acevedo, Paolo Frumento, Catharina Johansson, Lisa Eick, Nikos Papadogiannakis, et al. "Epigenetic Modifications in Placenta are Associated with the Child’s Sensitization to Allergens." BioMed Research International 2019 (April 17, 2019): 1–11. http://dx.doi.org/10.1155/2019/1315257.
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Prenatal environmental exposures are considered to contribute to the development of allergic sensitization by epigenetic mechanisms. The role of histone acetylation in the placenta has not been examined yet. We hypothesized that placental histone acetylation at the promoter regions of allergy-related immune regulatory genes is associated with the development of sensitization to allergens in the child. Histones H3 and H4 acetylation at the promoter regions of 6 selected allergy-related immune regulatory genes was assessed by a chromatin immunoprecipitation assay in 173 term placentas collected in the prospective birth-cohort ALADDIN. The development of IgE sensitization to allergens in the children was followed from 6 months up to 5 years of age. We discovered significant associations of histone acetylation levels with decreased risk of allergic sensitization in 3 genes. Decreased risk of sensitization to food allergens was associated with higher H3 acetylation levels in placentas at the IFNG and SH2B3 genes, and for H4 acetylation in HDAC4. Higher HDAC4 H4 acetylation levels were also associated with a decreased risk of sensitization to aeroallergens. In conclusion, our results suggest that acetylation of histones in placenta has a potential to predict the development of sensitization to allergens in children.
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Bertos, Nicholas R., Audrey H. Wang, and Xiang-Jiao Yang. "Class II histone deacetylases: Structure, function, and regulation." Biochemistry and Cell Biology 79, no. 3 (June 1, 2001): 243–52. http://dx.doi.org/10.1139/o01-032.
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Acetylation of histones, as well as non-histone proteins, plays important roles in regulating various cellular processes. Dynamic control of protein acetylation levels in vivo occurs through the opposing actions of histone acetyltransferases and histone deacetylases (HDACs). In the past few years, distinct classes of HDACs have been identified in mammalian cells. Class I members, such as HDAC1, HDAC2, HDAC3, and HDAC8, are well-known enzymatic transcriptional corepressors homologous to yeast Rpd3. Class II members, including HDAC4, HDAC5, HDAC6, HDAC7, and HDAC9, possess domains similar to the deacetylase domain of yeast Hda1. HDAC4, HDAC5, and HDAC7 function as transcriptional corepressors that interact with the MEF2 transcription factors and the N-CoR, BCoR, and CtBP corepressors. Intriguingly, HDAC4, HDAC5, and probably HDAC7 are regulated through subcellular compartmentalization controlled by site-specific phosphorylation and binding of 14-3-3 proteins; the regulation of these HDACs is thus directly linked to cellular signaling networks. Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions. Comprehension of the structure, function, and regulation of class II deacetylases is important for elucidating how acetylation regulates functions of histones and other proteins in vivo.Key words: histone acetylation, protein acetylation, histone deacetylase, 14-3-3 proteins.
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Lee, Yuri, Mi Hee Shin, Min-Kyoung Kim, Yeon Kyung Kim, Hye Sun Shin, Dong Hun Lee, and Jin Ho Chung. "Increased Histone Acetylation and Decreased Expression of Specific Histone Deacetylases in Ultraviolet-Irradiated and Intrinsically Aged Human Skin In Vivo." International Journal of Molecular Sciences 22, no. 4 (February 18, 2021): 2032. http://dx.doi.org/10.3390/ijms22042032.
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Histone deacetylases (HDACs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins and play a crucial role in epigenetic regulation. Previously, we showed that histone acetylation is implicated in ultraviolet (UV)-induced inflammation and matrix impairment. To elucidate the histone acetylation status and specific HDACs involved in skin aging, we examined the changes in histone acetylation, global HDAC activity, and the expression of HDACs and sirtuins (SIRTs) in intrinsically aged and photoaged human skin as well as in UV-irradiated human skin in vivo. Following acute UV irradiation, the acetylated histone H3 (AcH3) level was increased, but HDAC activity and the expression levels of HDAC4, HDAC11, and SIRT4 were significantly decreased. In intrinsically aged skin, AcH3 levels were increased, but HDAC activity and the expression levels of HDAC4, HDAC5, HDAC10, HDAC11, SIRT6, and SIRT7 were significantly decreased. However, histone acetylation and HDAC expression in photoaged skin were not significantly different from those in intrinsically aged skin. Collectively, HDAC4 and HDAC11 were decreased in both UV-irradiated and intrinsically aged skin, suggesting that they may play a universal role in increased histone acetylation associated with skin aging.
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Zhu, Liqian, Xinyi Jiang, Xiaotian Fu, Yanhua Qi, and Guoqiang Zhu. "The Involvement of Histone H3 Acetylation in Bovine Herpesvirus 1 Replication in MDBK Cells." Viruses 10, no. 10 (September 27, 2018): 525. http://dx.doi.org/10.3390/v10100525.
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During bovine herpesvirus 1 (BoHV-1) productive infection in cell cultures, partial of intranuclear viral DNA is present in nucleosomes, and viral protein VP22 associates with histones and decreases histone H4 acetylation, indicating the involvement of histone H4 acetylation in virus replication. In this study, we demonstrated that BoHV-1 infection at the late stage (at 24 h after infection) dramatically decreased histone H3 acetylation [at residues K9 (H3K9ac) and K18 (H3K18ac)], which was supported by the pronounced depletion of histone acetyltransferases (HATs) including CBP/P300 (CREB binding protein and p300), GCN5L2 (general control of amino acid synthesis yeast homolog like 2) and PCAF (P300/CBP-associated factor). The depletion of GCN5L2 promoted by virus infection was partially mediated by ubiquitin-proteasome pathway. Interestingly, the viral replication was enhanced by HAT (histone acetyltransferase) activator CTPB [N-(4-Chloro-3-trifluoromethylphenyl)-2-ethoxy-6-pentadecylbenzamide], and vice versa, inhibited by HAT inhibitor Anacardic acid (AA), suggesting that BoHV-1 may take advantage of histone acetylation for efficient replication. Taken together, we proposed that the HAT-dependent histone H3 acetylation plays an important role in BoHV-1 replication in MDBK (Madin-Darby bovine kidney) cells.
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Ge, Zhongqi, Devi Nair, Xiaoyan Guan, Neha Rastogi, Michael A. Freitas, and Mark R. Parthun. "Sites of Acetylation on Newly Synthesized Histone H4 Are Required for Chromatin Assembly and DNA Damage Response Signaling." Molecular and Cellular Biology 33, no. 16 (June 17, 2013): 3286–98. http://dx.doi.org/10.1128/mcb.00460-13.
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The best-characterized acetylation of newly synthesized histone H4 is the diacetylation of the NH2-terminal tail on lysines 5 and 12. Despite its evolutionary conservation, this pattern of modification has not been shown to be essential for either viability or chromatin assembly in any model organism. We demonstrate that mutations in histone H4 lysines 5 and 12 in yeast confer hypersensitivity to replication stress and DNA-damaging agents when combined with mutations in histone H4 lysine 91, which has also been found to be a site of acetylation on soluble histone H4. In addition, these mutations confer a dramatic decrease in cell viability when combined with mutations in histone H3 lysine 56. We also show that mutation of the sites of acetylation on newly synthesized histone H4 results in defects in the reassembly of chromatin structure that accompanies the repair of HO-mediated double-strand breaks. This defect is not due to a decrease in the level of histone H3 lysine 56 acetylation. Intriguingly, mutations that alter the sites of newly synthesized histone H4 acetylation display a marked decrease in levels of phosphorylated H2A (γ-H2AX) in chromatin surrounding the double-strand break. These results indicate that the sites of acetylation on newly synthesized histones H3 and H4 can function in nonoverlapping ways that are required for chromatin assembly, viability, and DNA damage response signaling.
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Calestagne-Morelli, Alison, and Juan Ausió. "Long-range histone acetylation: biological significance, structural implications, and mechanismsThis paper is one of a selection of papers published in this Special Issue, entitled 27th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 84, no. 4 (August 2006): 518–27. http://dx.doi.org/10.1139/o06-067.
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Genomic characterization of various euchromatic regions in higher eukaryotes has revealed that domain-wide hyperacetylation (over several kb) occurs at a range of loci, including individual genes, gene family clusters, compound clusters, and more general clusters of unrelated genes. Patterns of long-range histone hyperacetylation are strictly conserved within each unique cellular system studied and they reflect biological variability in gene regulation. Domain-wide histone acetylation consists generally of nonuniform peaks of enriched hyperacetylation of specific core histones, histone isoforms, and (or) histone variants against a backdrop of nonspecific acetylation across the domain in question. Here we review the characteristics of long-range histone acetylation in some higher eukaryotes and draw special attention to recent literature on the multiple effects that histone hyperacetylation has on chromatin’s structural integrity and how they affect transcription. These include the thermal, ionic, cumulative, and isoform-specific (H4 K16) consequences of acetylation that result in a more dynamic core complex and chromatin fiber.
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Drury, Georgina E., Adam A. Dowle, David A. Ashford, Wanda M. Waterworth, Jerry Thomas, and Christopher E. West. "Dynamics of plant histone modifications in response to DNA damage." Biochemical Journal 445, no. 3 (July 13, 2012): 393–401. http://dx.doi.org/10.1042/bj20111956.
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DNA damage detection and repair take place in the context of chromatin, and histone proteins play important roles in these events. Post-translational modifications of histone proteins are involved in repair and DNA damage signalling processes in response to genotoxic stresses. In particular, acetylation of histones H3 and H4 plays an important role in the mammalian and yeast DNA damage response and survival under genotoxic stress. However, the role of post-translational modifications to histones during the plant DNA damage response is currently poorly understood. Several different acetylated H3 and H4 N-terminal peptides following X-ray treatment were identified using MS analysis of purified histones, revealing previously unseen patterns of histone acetylation in Arabidopsis. Immunoblot analysis revealed an increase in the relative abundance of the H3 acetylated N-terminus, and a global decrease in hyperacetylation of H4 in response to DNA damage induced by X-rays. Conversely, mutants in the key DNA damage signalling factor ATM (ATAXIA TELANGIECTASIA MUTATED) display increased histone acetylation upon irradiation, linking the DNA damage response with dynamic changes in histone modification in plants.
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Zhao, Youshan, Feng Xu, Juan Guo, Sida Zhao, Chunkang Chang, and Xiao Li. "Dysregulation of ANKRD11 Influenced Hematopoisis By Histone Acetylation-Mediated Gene Expression in Myelodysplastic Syndrome." Blood 128, no. 22 (December 2, 2016): 4292. http://dx.doi.org/10.1182/blood.v128.22.4292.4292.
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Abstract Background and Object In addition to histone deacetylation, the importance of histone over-acetylation induced oncogene transcription in initiation and progression of myelodysplastic syndrome (MDS) has been proposed recently. Our previous whole-exome sequencing identified a new somatic mutation, ANKRD11, an important factor in histone acetylation regulation. Its roles in MDS pathophysiology need to be clarified. Methods The next generation target sequencing (Including ANKRD11) was carried out in 320 patients with MDS using the MiSeq Benchtop Sequencer. ANKRD11 mRNA expression in bone marrow of MDS was measured by real-time PCR. Loss and gain of function assay were carried out in myeloid cell lines K562, MEG-01£¬or SKM-1 to observe the influence on cell proliferation and differentiation . The levels of histone acetylation at H3 and H4 were detected by Western blot. Results Target sequencing in a cohort of 320 MDS patients identified 14 of ANKRD11 mutations (4.38%, Fig.1), which were confirmed by Sanger sequencing. Meanwhile, no ANKRD11 mutations in 100 normal controls were defined. ANKRD11 mutations occurred frequently in exons 10 and 9. The mRNA expression levels of ANKRD11 were significantly decreased in MDS patients, especially in ANKRD11mutant patients (Fig.2). ANKRD11 knockdown in K562 and MEG-1 resulted in growth inhibition, cell cycle arrest and erythroid/megakaryocytic differentiation retardant. In MDS cell line SKM-1, the arrested differentiation was rescued by over-expression of ANKRD11. Consistent with a role for ANKRD11 in histone acetylation, ANKRD11 KD increased acetylation of histones H3 and H4 at H3K14 and H4K5 and resulted in the upregulation of genes involved in differentiation inhibilation (SOX6, P21, et al). Finally, the ANKRD11 KD-mediated influence on cell proliferation and differentiation were reversed by inhibiting histone acetyltransferase activity. Conclusion Our assay defined that ANKRD11 was a crucial chromatin regulator that suppress histone acetylation and then decrease gene expression during myeloid differentiation, providing a likely explanation for its role in MDS pathogenesis. This study further support histone acetylase inhibitor as a potential treatment in MDS. Figure ANKRD11mutation distribution (a) and coexist with other mutations (b). Figure. ANKRD11mutation distribution (a) and coexist with other mutations (b). Figure The mRNA expression levels of ANKRD11in our MDS (A, C) subset and GEO data (B). Figure. The mRNA expression levels of ANKRD11in our MDS (A, C) subset and GEO data (B). Changes of histone acetylation in ANKRD11-KD cell line (MEG-01). ANKRD11 KD significantly increased acetylation of histones H3 and H4 at H3K14 and H4K5. Changes of histone acetylation in ANKRD11-KD cell line (MEG-01). ANKRD11 KD significantly increased acetylation of histones H3 and H4 at H3K14 and H4K5. Disclosures No relevant conflicts of interest to declare.
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Waterborg, Jakob H. "Dynamics of histone acetylation in vivo. A function for acetylation turnover?" Biochemistry and Cell Biology 80, no. 3 (June 1, 2002): 363–78. http://dx.doi.org/10.1139/o02-080.
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Histone acetylation, discovered more than 40 years ago, is a reversible modification of lysines within the amino-terminal domain of core histones. Amino-terminal histone domains contribute to the compaction of genes into repressed chromatin fibers. It is thought that their acetylation causes localized relaxation of chromatin as a necessary but not sufficient condition for processes that repackage DNA such as transcription, replication, repair, recombination, and sperm formation. While increased histone acetylation enhances gene transcription and loss of acetylation represses and silences genes, the function of the rapid continuous or repetitive acetylation and deacetylation reactions with half-lives of just a few minutes remains unknown. Thirty years of in vivo measurements of acetylation turnover and rates of change in histone modification levels have been reviewed to identify common chromatin characteristics measured by distinct protocols. It has now become possible to look across a wider spectrum of organisms than ever before and identify common features. The rapid turnover rates in transcriptionally active and competent chromatin are one such feature. While ubiquitously observed, we still do not know whether turnover itself is linked to chromatin transcription beyond its contribution to rapid changes towards hyper- or hypoacetylation of nucleosomes. However, recent experiments suggest that turnover may be linked directly to steps in gene transcription, interacting with nucleosome remodeling complexes.Key words: histone, acetylation, turnover, chromatin, transcription.
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Vermeulen, Michiel, Michael J. Carrozza, Edwin Lasonder, Jerry L. Workman, Colin Logie, and Hendrik G. Stunnenberg. "In Vitro Targeting Reveals Intrinsic Histone Tail Specificity of the Sin3/Histone Deacetylase and N-CoR/SMRT Corepressor Complexes." Molecular and Cellular Biology 24, no. 6 (March 15, 2004): 2364–72. http://dx.doi.org/10.1128/mcb.24.6.2364-2372.2004.
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ABSTRACT The histone code is among others established via differential acetylation catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). To unambiguously determine the histone tail specificity of HDAC-containing complexes, we have established an in vitro system consisting of nucleosomal templates reconstituted with hyperacetylated histones or recombinant histones followed by acetylation with native SAGA or NuA4. Selective targeting of the mammalian Sin3/HDAC and N-CoR/SMRT corepressor complexes by using specific chimeric repressors created a near physiological setting to assess their histone tail specificity. Recruitment of the Sin3/HDAC complex to nucleosomal templates preacetylated with SAGA or NuA4 resulted in deacetylation of histones H3 and H4, whereas recruitment of N-CoR/SMRT resulted in deacetylation of histone H3 only. These results provide solid evidence that HDAC-containing complexes display distinct, intrinsic histone tail specificities and hence may function differently to regulate chromatin structure and transcription.
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Tamburini, Beth A., and Jessica K. Tyler. "Localized Histone Acetylation and Deacetylation Triggered by the Homologous Recombination Pathway of Double-Strand DNA Repair." Molecular and Cellular Biology 25, no. 12 (June 15, 2005): 4903–13. http://dx.doi.org/10.1128/mcb.25.12.4903-4913.2005.
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ABSTRACT Many recent studies have demonstrated recruitment of chromatin-modifying enzymes to double-strand breaks. Instead, we wanted to examine chromatin modifications during the repair of these double-strand breaks. We show that homologous recombination triggers the acetylation of N-terminal lysines on histones H3 and H4 flanking a double-strand break, followed by deacetylation of H3 and H4. Consistent with a requirement for acetylation and deacetylation during homologous recombination, Saccharomyces cerevisiae with substitutions of the acetylatable lysines of histone H4, deleted for the N-terminal tail of histone H3 or H4, deleted for the histone acetyltransferase GCN5 gene or the histone deacetylase RPD3 gene, shows inviability following induction of an HO lesion that is repaired primarily by homologous recombination. Furthermore, the histone acetyltransferases Gcn5 and Esa1 and the histone deacetylases Rpd3, Sir2, and Hst1 are recruited to the HO lesion during homologous recombinational repair. We have also observed a distinct pattern of histone deacetylation at the donor locus during homologous recombination. Our results demonstrate that dynamic changes in histone acetylation accompany homologous recombination and that the ability to modulate histone acetylation is essential for viability following homologous recombination.
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Alam, Shah, Antonia Piazzesi, Mariam Abd El Fatah, Maren Raucamp, and Gerhild van Echten-Deckert. "Neurodegeneration Caused by S1P-Lyase Deficiency Involves Calcium-Dependent Tau Pathology and Abnormal Histone Acetylation." Cells 9, no. 10 (September 28, 2020): 2189. http://dx.doi.org/10.3390/cells9102189.
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We have shown that sphingosine 1-phosphate (S1P) generated by sphingosine kinase 2 (SK2) is toxic in neurons lacking S1P-lyase (SGPL1), the enzyme that catalyzes its irreversible cleavage. Interestingly, patients harboring mutations in the gene encoding this enzyme (SGPL1) often present with neurological pathologies. Studies in a mouse model with a developmental neural-specific ablation of SGPL1 (SGPL1fl/fl/Nes) confirmed the importance of S1P metabolism for the presynaptic architecture and neuronal autophagy, known to be essential for brain health. We now investigated in SGPL1-deficient murine brains two other factors involved in neurodegenerative processes, namely tau phosphorylation and histone acetylation. In hippocampal and cortical slices SGPL1 deficiency and hence S1P accumulation are accompanied by hyperphosphorylation of tau and an elevated acetylation of histone3 (H3) and histone4 (H4). Calcium chelation with BAPTA-AM rescued both tau hyperphosphorylation and histone acetylation, designating calcium as an essential mediator of these (patho)physiological functions of S1P in the brain. Studies in primary cultured neurons and astrocytes derived from SGPL1fl/fl/Nes mice revealed hyperphosphorylated tau only in SGPL1-deficient neurons and increased histone acetylation only in SGPL1-deficient astrocytes. Both could be reversed to control values with BAPTA-AM, indicating the close interdependence of S1P metabolism, calcium homeostasis, and brain health.
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Ito, Kazuhiro, and Ian M. Adcock. "Histone Acetylation and Histone Deacetylation." Molecular Biotechnology 20, no. 1 (2002): 099–106. http://dx.doi.org/10.1385/mb:20:1:099.
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Romhányi, Dóra, Kornélia Szabó, Lajos Kemény, and Gergely Groma. "Histone and Histone Acetylation-Related Alterations of Gene Expression in Uninvolved Psoriatic Skin and Their Effects on Cell Proliferation, Differentiation, and Immune Responses." International Journal of Molecular Sciences 24, no. 19 (September 26, 2023): 14551. http://dx.doi.org/10.3390/ijms241914551.
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Psoriasis is a chronic immune-mediated skin disease in which the symptom-free, uninvolved skin carries alterations in gene expression, serving as a basis for lesion formation. Histones and histone acetylation-related processes are key regulators of gene expression, controlling cell proliferation and immune responses. Dysregulation of these processes is likely to play an important role in the pathogenesis of psoriasis. To gain a complete overview of these potential alterations, we performed a meta-analysis of a psoriatic uninvolved skin dataset containing differentially expressed transcripts from nearly 300 individuals and screened for histones and histone acetylation-related molecules. We identified altered expression of the replication-dependent histones HIST2H2AA3 and HIST2H4A and the replication-independent histones H2AFY, H2AFZ, and H3F3A/B. Eight histone chaperones were also identified. Among the histone acetyltransferases, ELP3 and KAT5 and members of the ATAC, NSL, and SAGA acetyltransferase complexes are affected in uninvolved skin. Histone deacetylation-related alterations were found to affect eight HDACs and members of the NCOR/SMRT, NURD, SIN3, and SHIP HDAC complexes. In this article, we discuss how histone and histone acetylation-related expression changes may affect proliferation and differentiation, as well as innate, macrophage-mediated, and T cell-mediated pro- and anti-inflammatory responses, which are known to play a central role in the development of psoriasis.
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Topalidou, Irini, Manolis Papamichos-Chronakis, and George Thireos. "Post-TATA Binding Protein Recruitment Clearance of Gcn5-Dependent Histone Acetylation within Promoter Nucleosomes." Molecular and Cellular Biology 23, no. 21 (November 1, 2003): 7809–17. http://dx.doi.org/10.1128/mcb.23.21.7809-7817.2003.
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ABSTRACT Transcriptional activation of eukaryotic genes often requires the function of histone acetyltransferases (HATs), which is expected to result in the hyperacetylation of histones within promoter nucleosomes. In this study we show that, in Saccharomyces cerevisiae, the steady-state levels of Gcn5-dependent histone acetylation within a number of transcriptionally active promoters are inversely related to the rate of transcription. High acetylation levels were measured only when transcription was attenuated either by TATA element mutations or in a strain carrying a temperature-sensitive protein component of RNA polymerase II. In addition, we show that in one case the low levels of histone acetylation depend on the function of the Rpd3 histone deacetylase. These results point to the existence of an unexpected interplay of two opposing histone-modifying activities which operate on promoter nucleosomes following the initiation of RNA synthesis. Such interplay could ensure rapid turnover of chromatin acetylation states in continuously reprogrammed transcriptional systems.
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Tao, Dan, Jun Lu, Hui Sun, Yan-Mei Zhao, Zhi-Gen Yuan, Xiao-Xue Li, and Bai-Qu Huang. "Trichostatin A Extends the Lifespan of Drosophila melanogaster by Elevating hsp22 Expression." Acta Biochimica et Biophysica Sinica 36, no. 9 (September 1, 2004): 618–22. http://dx.doi.org/10.1093/abbs/36.9.618.
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Abstract The level of acetylation of histones in nucleosomes is related to the longevity of yeast and animals. However, the mechanisms by which acetylation and deacetylation affect longevity remain unclear. In present study, we investigated the influence of histone acetylation modification on the expression of hsp22 gene and the lifespan in Drosophila melanogaster using histone deacetylase (HDAC) inhibitor Trichostatin A (TSA). The results showed that TSA could extend the lifespan of Drosophila melanogaster. Furthermore, TSA significantly promoted the hsp22 gene transcription, and affected the chromatin morphology at the locus of hsp22 gene along the polytene chromosome. Present data implicate that TSA may affect the lifespan of Drosophila through changing the level of histone acetylation and influencing the expression of hsp22 gene that is related to aging.
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Gómez, Eliana B., Joaquín M. Espinosa, and Susan L. Forsburg. "Schizosaccharomyces pombe mst2+ Encodes a MYST Family Histone Acetyltransferase That Negatively Regulates Telomere Silencing." Molecular and Cellular Biology 25, no. 20 (October 15, 2005): 8887–903. http://dx.doi.org/10.1128/mcb.25.20.8887-8903.2005.
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ABSTRACT Histone acetylation and deacetylation are associated with transcriptional activity and the formation of constitutively silent heterochromatin. Increasingly, histone acetylation is also implicated in other chromosome transactions, including replication and segregation. We have cloned the only Schizosaccharomyces pombe MYST family histone acetyltransferase genes, mst1 + and mst2 +. Mst1p, but not Mst2p, is essential for viability. Both proteins are localized to the nucleus and bound to chromatin throughout the cell cycle. Δmst2 genetically interacts with mutants that affect heterochromatin, cohesion, and telomere structure. Mst2p is a negative regulator of silencing at the telomere but does not affect silencing in the centromere or mating type region. We generated a census of proteins and histone modifications at wild-type telomeres. A histone acetylation gradient at the telomeres is lost in Δmst2 cells without affecting the distribution of Taz1p, Swi6p, Rad21p, or Sir2p. We propose that the increased telomeric silencing is caused by histone hypoacetylation and/or an increase in the ratio of methylated to acetylated histones. Although telomere length is normal, meiosis is aberrant in Δmst2 diploid homozygote mutants, suggesting that telomeric histone acetylation contributes to normal meiotic progression.
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Lin, R., J. W. Leone, R. G. Cook, and C. D. Allis. "Antibodies specific to acetylated histones document the existence of deposition- and transcription-related histone acetylation in Tetrahymena." Journal of Cell Biology 108, no. 5 (May 1, 1989): 1577–88. http://dx.doi.org/10.1083/jcb.108.5.1577.
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In this study, we have constructed synthetic peptides which are identical to hyperacetylated amino termini of two Tetrahymena core histones (tetra-acetylated H4 and penta-acetylated hv1) and used them to generate polyclonal antibodies specific for acetylated forms (mono-, di-, tri-, etc.) of these histones. Neither of these antisera recognizes histone that is unacetylated. Immunoblotting analyses demonstrate that both transcription-related and deposition-related acetate groups on H4 are recognized by both antisera. In addition, the antiserum raised against penta-acetylated hv1 also recognizes acetylated forms of this variant. Immunofluorescent analyses with both antisera demonstrate that, as expected, histone acetylation is specific to macronuclei (or new macronuclei) at all stages of the life cycle except when micronuclei undergo periods of rapid replication and chromatin assembly. During this time micronuclear staining is also detected. Our results also suggest that transcription-related acetylation begins selectively in new macronuclei immediately after the second postzygotic division. Acetylated histone is not observed in new micronuclei during stages corresponding to anlagen development and, therefore, histone acetylation can be distributed asymmetrically in development. Equally striking is the rapid turnover of acetylated histone in parental macronuclei during the time of their inactivation and elimination from the cell. Taken together, these data lend strong support to the idea that modulation of histone acetylation plays an important role in gene activation and in chromatin assembly.
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Fang, Lei, Danqi Chen, Clinton Yu, Hongjie Li, Jason Brocato, Lan Huang, and Chunyuan Jin. "Mechanisms Underlying Acrolein-Mediated Inhibition of Chromatin Assembly." Molecular and Cellular Biology 36, no. 23 (September 26, 2016): 2995–3008. http://dx.doi.org/10.1128/mcb.00448-16.
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Acrolein is a major component of cigarette smoke and cooking fumes. Previously, we reported that acrolein compromises chromatin assembly; however, underlying mechanisms have not been defined. Here, we report that acrolein reacts with lysine residues, including lysines 5 and 12, sites important for chromatin assembly, on histone H4 in vitro and in vivo . Acrolein-modified histones are resistant to acetylation, suggesting that the reduced H4K12 acetylation that occurs following acrolein exposure is probably due to the formation of acrolein-histone lysine adducts. Accordingly, the association of H3/H4 with the histone chaperone ASF1 and importin 4 is disrupted and the translocation of green fluorescent protein-tagged H3 is inhibited in cells exposed to acrolein. Interestingly, in vitro plasmid supercoiling assays revealed that treatment of either histones or ASF1 with acrolein has no effect on the formation of plasmid supercoiling, indicating that acrolein-protein adduct formation itself does not directly interfere with nucleosome assembly. Notably, exposure of histones to acrolein prior to histone acetylation leads to the inhibition of remodeling and spacing factor chromatin assembly, which requires acetylated histones for efficient assembly. These results suggest that acrolein compromises chromatin assembly by reacting with histone lysine residues at the sites critical for chromatin assembly and prevents these sites from physiological modifications.
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Vezzoli, Marco, Lara Isabel de Llobet Cucalon, Chiara Di Vona, Marco Morselli, Barbara Montanini, Susana de la Luna, Martin Teichmann, Giorgio Dieci, and Roberto Ferrari. "TFIIIC as a Potential Epigenetic Modulator of Histone Acetylation in Human Stem Cells." International Journal of Molecular Sciences 24, no. 4 (February 11, 2023): 3624. http://dx.doi.org/10.3390/ijms24043624.
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Regulation of histone acetylation dictates patterns of gene expression and hence cell identity. Due to their clinical relevance in cancer biology, understanding how human embryonic stem cells (hESCs) regulate their genomic patterns of histone acetylation is critical, but it remains largely to be investigated. Here, we provide evidence that acetylation of histone H3 lysine-18 (H3K18ac) and lysine-27 (H3K27ac) is only partially established by p300 in stem cells, while it represents the main histone acetyltransferase (HAT) for these marks in somatic cells. Our analysis reveals that whereas p300 marginally associated with H3K18ac and H3K27ac in hESCs, it largely overlapped with these histone marks upon differentiation. Interestingly, we show that H3K18ac is found at “stemness” genes enriched in RNA polymerase III transcription factor C (TFIIIC) in hESCs, whilst lacking p300. Moreover, TFIIIC was also found in the vicinity of genes involved in neuronal biology, although devoid of H3K18ac. Our data suggest a more complex pattern of HATs responsible for histone acetylations in hESCs than previously considered, suggesting a putative role for H3K18ac and TFIIIC in regulating “stemness” genes as well as genes associated with neuronal differentiation of hESCs. The results break ground for possible new paradigms for genome acetylation in hESCs that could lead to new avenues for therapeutic intervention in cancer and developmental diseases.
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Harrison, Charlotte. "Targeting histone acetylation." Nature Reviews Drug Discovery 9, no. 9 (September 2010): 681. http://dx.doi.org/10.1038/nrd3261.
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Benton, Christopher B., Warren Fiskus, and Kapil N. Bhalla. "Targeting Histone Acetylation." Cancer Journal 23, no. 5 (2017): 286–91. http://dx.doi.org/10.1097/ppo.0000000000000284.
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Zerzaihi, Ouafa, Sabrina Chriett, Hubert Vidal, and Luciano Pirola. "Insulin-dependent transcriptional control in L6 rat myotubes is associated with modulation of histone acetylation and accumulation of the histone variant H2A.Z in the proximity of the transcriptional start site." Biochemistry and Cell Biology 92, no. 1 (February 2014): 61–67. http://dx.doi.org/10.1139/bcb-2013-0071.
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Besides its direct metabolic effects, insulin induces transcriptional alterations in its target tissues. However, whether such changes are accompanied by epigenetic changes on the chromatin template encompassing insulin responsive genes is unclear. Here, mRNA levels of insulin-responsive genes hexokinase 2 (Hk2), insulin receptor substrate (Irs2), and the PI3K subunit p85β (Pik3r2) were compared in control versus insulin-stimulated L6 myotubes. Chromatin immunoprecipitation (ChIP) was performed with antibodies directed to histone H2A, histone variant H2A.Z, acetylated histone H3 on lysines 9/14, and acetylated H2A.Z. Insulin induced a more than 2-fold Hk2 mRNA increase, while Irs2 and Pik3r2 were downregulated. ChIP to H2A and H2A.Z showed higher H2A.Z accumulation around the transcriptional start site (TSS) of these insulin-modulated genes, while H2A.Z accumulation was lower distally to the TSS in the Hk2 promoter. H2A.Z levels and H3K9/14 acetylation correlated on several loci along the Hk2 gene, and H3K9/14 as well as H2A.Z acetylation was enhanced by insulin treatment. On the contrary, reduced H3K9/14 acetylation was observed in insulin-repressed Irs2 and Pik3r2, and recovery of acetylation by treatment with the histone deacetylase inhibitor trichostatin A reverted insulin-induced Irs2 downregulation. The chromatin regions encompassing selected insulin-responsive genes are thus featured by accumulation of H2A.Z around the TSS. H2A.Z accumulation facilitates insulin-dependent modulation of pharmacologically treatable H3K9/14 and H2A.Z acetylations. Indeed, inhibition of histone deacetylases by TSA treatment reverted insulin induced Irs2 gene downregulation. Dysregulated histone acetylation may thus be potentially targeted with histone deacetylase inhibitors.
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Letting, Danielle L., Carrie Rakowski, Mitchell J. Weiss, and Gerd A. Blobel. "Formation of a Tissue-Specific Histone Acetylation Pattern by the Hematopoietic Transcription Factor GATA-1." Molecular and Cellular Biology 23, no. 4 (February 15, 2003): 1334–40. http://dx.doi.org/10.1128/mcb.23.4.1334-1340.2003.
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ABSTRACT One function of lineage-restricted transcription factors may be to control the formation of tissue-specific chromatin domains. In erythroid cells, the β-globin gene cluster undergoes developmentally regulated hyperacetylation of histones at the active globin genes and the locus control region (LCR). However, it is unknown which transcription factor(s) governs the establishment of this erythroid-specific chromatin domain. We measured histone acetylation at the β-globin locus in the erythroid cell line G1E, which is deficient for the essential hematopoietic transcription factor GATA-1. Restoration of GATA-1 activity in G1E cells led to a substantial increase in acetylation of histones H3 and H4 at the β-globin promoter and the LCR. Time course experiments showed that histone acetylation occurred rapidly after GATA-1 activation and coincided with globin gene expression, indicating that the effects of GATA-1 are direct. Moreover, increases in histone acetylation correlated with occupancy of GATA-1 and the acetyltransferase CBP at the locus in vivo. Together, these results suggest that GATA-1 and its cofactor CBP are essential for the formation of an erythroid-specific acetylation pattern that is permissive for high levels of gene expression.
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Teresa, Benilde García-de, Cecilia Ayala-Zambrano, Mirna González-Suárez, Bertha Molina, Leda Torres, Alfredo Rodríguez, and Sara Frías. "Reversion from basal histone H4 hypoacetylation at the replication fork increases DNA damage in FANCA deficient cells." PLOS ONE 19, no. 5 (May 31, 2024): e0298032. http://dx.doi.org/10.1371/journal.pone.0298032.
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The FA/BRCA pathway safeguards DNA replication by repairing interstrand crosslinks (ICL) and maintaining replication fork stability. Chromatin structure, which is in part regulated by histones posttranslational modifications (PTMs), has a role in maintaining genomic integrity through stabilization of the DNA replication fork and promotion of DNA repair. An appropriate balance of PTMs, especially acetylation of histones H4 in nascent chromatin, is required to preserve a stable DNA replication fork. To evaluate the acetylation status of histone H4 at the replication fork of FANCA deficient cells, we compared histone acetylation status at the DNA replication fork of isogenic FANCA deficient and FANCA proficient cell lines by using accelerated native immunoprecipitation of nascent DNA (aniPOND) and in situ protein interactions in the replication fork (SIRF) assays. We found basal hypoacetylation of multiple residues of histone H4 in FA replication forks, together with increased levels of Histone Deacetylase 1 (HDAC1). Interestingly, high-dose short-term treatment with mitomycin C (MMC) had no effect over H4 acetylation abundance at the replication fork. However, chemical inhibition of histone deacetylases (HDAC) with Suberoylanilide hydroxamic acid (SAHA) induced acetylation of the FANCA deficient DNA replication forks to levels comparable to their isogenic control counterparts. This forced permanence of acetylation impacted FA cells homeostasis by inducing DNA damage and promoting G2 cell cycle arrest. Altogether, this caused reduced RAD51 foci formation and increased markers of replication stress, including phospho-RPA-S33. Hypoacetylation of the FANCA deficient replication fork, is part of the cellular phenotype, the perturbation of this feature by agents that prevent deacetylation, such as SAHA, have a deleterious effect over the delicate equilibrium they have reached to perdure despite a defective FA/BRCA pathway.