Effects of histone acetylation on chromatin topology in vivo.

Lutter, Leonard C.; Judis, Luann; Paretti, Robert F.

doi:10.1128/mcb.12.11.5004

Cited by 67 publications

(55 citation statements)

References 60 publications

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“…Norton et al have shown in vitro, using subsaturated circular DNA templates, that acetylated nucleosomes constrain 20% fewer superhelical turns than unmodified nucleosomes (31,32). In contrast, in vivo there was no detectable effect of histone acetylation on the DNA topology of a simian virus 40 minichromosome (29). In vitro, with templates harboring a nucleosome density close to that found in the cell, it was shown that hyperacetylated chromatin resembles unmodified chromatin although it displayed a high degree of conformational flexibility, revealing profound alterations of histone-DNA interactions (22).…”

Section: Discussionmentioning

confidence: 99%

Role of Histone N-Terminal Tails and Their Acetylation in Nucleosome Dynamics

Morales¹,

Richard-Foy²

2000

Molecular and Cellular Biology

101

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Histone N-terminal tails are central to the processes that modulate nucleosome structure and function. We have studied the contribution of core histone tails to the structure of a single nucleosome and to a histone (H3-H4) 2 tetrameric particle assembled on a topologically constrained DNA minicircle. The effect of histone tail cleavage and histone tail acetylation on the structure of the nucleoprotein particle was investigated by analyzing the DNA topoisomer equilibrium after relaxation of DNA torsional stress by topoisomerase I. Removal of the H3 and H4 N-terminal tails, as well as their acetylation, provoked a dramatic change in the linking-number difference of the (H3-H4) 2 tetrameric particle, with a release of up to 70% of the negative supercoiling previously constrained by this structure. The (H3-H4) 2 tetramers containing tailless or hyperacetylated histones showed a striking preference for relaxed DNA over negatively supercoiled DNA. This argues in favor of a change in tetramer structure that constrains less DNA and adopts a relaxed flat conformation instead of its left-handed conformation within the nucleosome. In contrast neither removal or hyperacetylation of H3 and H4 tails nor removal or hyperacetylation of H2A and H2B N-terminal tails affected the nucleosome structure. This indicates that the globular domain of H2A and H2B is sufficient to stabilize the tailless or the hyperacetylated (H3-H4) 2 tetramer in a left-handed superhelix conformation. These results suggest that the effect of histone tail acetylation that facilitates transcription may be mediated via transient formation of an (H3-H4) 2 tetrameric particle that could adopt an open structure only when H3 and/or H4 tails are hyperacetylated.

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Section: Discussionmentioning

confidence: 99%

Role of Histone N-Terminal Tails and Their Acetylation in Nucleosome Dynamics

Morales¹,

Richard-Foy²

2000

Molecular and Cellular Biology

101

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“…Histone acetylation results in attenuation of the electrostatic charge interactions between histones and DNA and has been associated with chromatin decondensation (11,12,31). However, other studies postulate that histone acetylation alone may have minimal effects on chromatin structure (32). Epigenetic silencing is accomplished by condensation of the chromatin in the form of heterochromatin and has been associated with hypoacetylation and hypermethylation.…”

Section: Discussionmentioning

confidence: 99%

Valproic Acid Alters Chromatin Structure by Regulation of Chromatin Modulation Proteins

et al. 2005

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Histone acetylation and deacetylation are crucial in the regulation of gene expression. Dynamic changes in gene expression may affect chromatin structure and, consequently, the interaction of chromatin with regulatory factors. In this study, the effects of the antiseizure drug valproic acid (VPA) on the expression of genes that regulate the structure of chromatin and the access of macromolecules to the DNA were investigated. Exposure of breast cancer cells to VPA resulted in rapid dose-dependent hyperacetylation of the histones H3 and H4. VPA further induced a depletion of several members of the structural maintenance of chromatin (SMC) proteins, SMC-associated proteins, DNA methyltransferase, and heterochromatin proteins. Down-regulation of these proteins was associated with chromatin decondensation. The observed alterations of chromatin structure correlated with enhanced sensitivity of DNA to nucleases and increased interaction of DNA with intercalating agents. VPA-induced chromatin decondensation led to a sequence-specific potentiation of DNA-damaging agents in cell culture and xenograft models. Modulation of heterochromatin maintenance proteins was not a direct, but a downstream, effect of histone acetylation. The effects on the chromatin structure were reversible upon drug withdrawal, but obligatory for the potentiation of DNA-damaging agents. In addition to their antitumor activity as single agents, the chromatin decondensation induced by histone deacetylase inhibitors may enhance the efficacy of cytotoxic agents that act by targeting DNA. The proposed mechanism of action suggests an effect of drug sequencing on the antitumor activity of these drugs. (Cancer Res 2005; 65(9): 3815-22)

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“…The high positive charge of the amino-terminal domains may be important in shielding the negatively charged DNA phosphate backbone during compaction (Manning 1978;Widom 1986;Clark and Kimura 1990). Hyperacetylation of histones H3 and H4 directly alters the linking number of circular minichromosomes reconstituted in vitro (Norton et al 1989, likely through subtle changes in core particle shape {Bauer et al 1994), and similar changes may be detected in vivo (Thomsen et al 1991; but see also Lutter et al 1992). Thus, dynamic alterations in histone acetylation states are expected to play critical roles in the remodeling of chromatin that must accompany many nuclear processes.…”

Section: }mentioning

confidence: 99%

Histone H4 and the maintenance of genome integrity.

Megee¹,

Morgan²,

Smith³

1995

Genes Dev.

158

112

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The normal progression of Saccharomyces cerevisiae through nuclear division requires the function of the amino-terminal domain of histone H4. Mutations that delete the domain, or alter 4 conserved lysine residues within the domain, cause a marked delay during the G2 +M phases of the cell cycle. Site-directed mutagenesis of single and multiple lysine residues failed to map this phenotype to any particular site; the defect was only observed when all four lysines were mutated. Starting with a quadruple lysine-to-glutamine substitution allele, the insertion of a tripeptide containing a single extra lysine residue suppressed the G2+M cell cycle defect. Thus, the amino-terminal domain of histone H4 has novel genetic functions that depend on the presence of lysine per se, and not a specific primary peptide sequence. To determine the nature of this function, we examined H4 mutants that were also defective for G2/M checkpoint pathways. Disruption of the mitotic spindle checkpoint pathway had no effect on the phenotype of the histone amino-terminal domain mutant. However, disruption of RADg, which is part of the pathway that monitors DNA integrity, caused precocious progression of the H4 mutant through nuclear division and increased cell death. These results indicate that the lysine-dependent function of histone H4 is required for the maintenance of genome integrity, and that DNA damage resulting from the loss of this function activates the RAD9-dependent G2/M checkpoint pathway.

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Effects of histone acetylation on chromatin topology in vivo.

Cited by 67 publications

References 60 publications

Role of Histone N-Terminal Tails and Their Acetylation in Nucleosome Dynamics

Role of Histone N-Terminal Tails and Their Acetylation in Nucleosome Dynamics

Valproic Acid Alters Chromatin Structure by Regulation of Chromatin Modulation Proteins

Histone H4 and the maintenance of genome integrity.

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