The role of histone variability in chromatin stability and folding

Ausió, Juan; Abbott, D. Wade

doi:10.1016/s0167-7306(03)39010-6

Cited by 14 publications

(17 citation statements)

References 405 publications

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“…Given the crucial role of the H3͞H4 histone tails, it is not surprising that these tails are excellent candidates for various forms of modifications constituting the so-called ''histone code.'' Indeed, Ϸ70% of all modifications, of which acetylation and methylation are the most common, occur on the H3 and H4 tails (1,5,31). Our prediction that the H2A͞H2B tails mediate fiber͞fiber interactions also agrees well with the experiments of Hansen and coworkers, who demonstrate that these tails are crucial for oligomerization of nucleosomal arrays at high salt concentrations, whereas the H3 and H4 tails are dispensable (7,13).…”

Section: Resultssupporting

confidence: 90%

Role of histone tails in chromatin folding revealed by a mesoscopic oligonucleosome model

Arya

Schlick

2006

Proc. Natl. Acad. Sci. U.S.A.

179

225

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The role of each histone tail in regulating chromatin structure is elucidated by using a coarse-grained model of an oligonucleosome incorporating flexible histone tails that reproduces the conformational and dynamical properties of chromatin. Specifically, a tailored configurational-bias Monte Carlo method that efficiently samples the possible conformational states of oligonucleosomes yields positional distributions of histone tails around nucleosomes and illuminates the nature of tail͞core͞DNA interactions at various salt milieus. Analyses indicate that the H4 histone tails are most important in terms of mediating internucleosomal interactions, especially in highly compact chromatin with linker histones, followed by H3, H2A, and H2B tails in decreasing order of importance. In addition to mediating internucleosomal interactions, the H3 histone tails crucially screen the electrostatic repulsion between the entering͞exiting DNA linkers. The H2A and H2B tails distribute themselves along the periphery of chromatin fibers and are important for mediating fiber͞fiber interactions. A delicate balance between tail-mediated internucleosomal attraction and repulsion among linker DNAs allows the entering͞exiting linker DNAs to align perpendicular to each other in linker-histone deficient chromatin, leading to the formation of an irregular zigzag-folded fiber with dominant pair-wise interactions between nucleosomes i and i ؎ 4.Monte Carlo simulations ͉ nucleosome ͉ DNA͞protein complexes ͉ chromatin structure regulation ͉ irregular zigzag E ukaryotic double-stranded DNA achieves cellular compaction through several hierarchical levels of organization (1). The most fundamental of these involves wrapping of DNA around protein aggregates known as nucleosomes. The nucleosome, whose structure has been determined at high resolution (2), comprises two copies each of the positively charged histones H2A, H2B, H3, and H4. A large portion of each histone chain forms the nucleosome core around which DNA makes Ϸ1.75 turns, whereas the terminal portion, the histone tail, extends outwards from the core and is much floppier than the rest of the nucleosome. The resulting ''beads-on-a-string'' nucleosome͞ DNA complex compacts further at physiological salt conditions and, in the presence of highly charged linker histone proteins (H1 or H5), forms the compact 30-nm chromatin fiber.The histone tails critically regulate chromatin compaction and function. Electrostatic arguments alone suggest that the compact state of chromatin can be achieved only if the strong DNA͞DNA repulsion as well as the entropic penalty loss associated with folding are alleviated. The positively charged histone tails provide the necessary driving force for folding by mediating favorable internucleosomal interactions and screening DNA repulsion. At the same time, gene activation requires that related regions of chromatin become partially unfolded to allow access to transcription machinery. Indeed, acetylation of histone tail residues through the action of histone acetyl trans...

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Section: Resultssupporting

confidence: 90%

Role of histone tails in chromatin folding revealed by a mesoscopic oligonucleosome model

Arya

Schlick

2006

Proc. Natl. Acad. Sci. U.S.A.

179

225

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“…9) is in contrast with the apparent lack of a role played by the histone tails in the UDG-APE system (15). However, our results are consistent with the notion that histone acetylation relaxes the nucleosome structure (7,21). This idea suggests the possibility that repair occurs faster in the highly acetylated regions of the genome, which often are associated with transcriptional activity (21).…”

Section: Discussionsupporting

confidence: 82%

MBD4-Mediated Glycosylase Activity on a Chromatin Template Is Enhanced by Acetylation

Ishibashi

Cupples

et al. 2008

Molecular and Cellular Biology

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The ability of the MBD4 glycosylase to excise a mismatched base from DNA has been assessed in vitro using DNA substrates with different extents of cytosine methylation, in the presence or absence of reconstituted nucleosomes. Despite the enhanced ability of MBD4 to bind to methylated cytosines, the efficiency of its glycosylase activity on T/G mismatches was slightly dependent on the extent of methylation of the DNA substrate. The reduction in activity caused by competitor DNA was likewise unaffected by the methylation status of the substrate or the competitor. Our results also show that MBD4 efficiently processed T/G mismatches within the nucleosome. Furthermore, the glycolytic activity of the enzyme was not affected by the positioning of the mismatch within the nucleosome. However, histone hyperacetylation facilitated the efficiency with which the bases were excised from the nucleosome templates, irrespective of the position of the mismatch relative to the pseudodyad axis of symmetry of the nucleosome.Diverse organisms, prokaryotic and eukaryotic, methylate selected cytosines in their genomes (reviewed by Bestor [19]). In bacteria, methylation is usually associated with restrictionmodification systems which protect the cell against attack from bacteriophages. Cytosine methylation is associated with genome defense in some eukaryotes, but it also plays vital roles in development and in the control of gene expression, to the extent that the homozygous knockout of cytosine methyltransferase genes in the mouse is an embryonic lethal mutation (40). Despite its importance, cytosine methylation imposes a genetic and epigenetic cost because 5-methylcytosines deaminate into thymine (reviewed in references 53 and 67). Unrepaired, the resulting T/G mismatches lead to CG-to-TA transition mutations. There is also evidence from work with Escherichia coli that 5-methylcytosines are more prone to mispairing during DNA replication than unmethylated bases and/or are less well repaired and that they are particularly susceptible to other forms of endogenous and exogenous damage which cause them to mispair (24, 54). A similar situation exists for eukaryotes (reviewed in reference 51).Whatever the cause, mutations at methylated cytosines may influence phenotype in two ways: (i) by introducing nonsense or missense mutations which alter the functions of proteins and (ii) by demethylating promoter regions and thereby altering patterns of gene expression. As one line of defense against the genetic and epigenetic effects of mutations associated with methylated cytosines, cells have developed repair systems specific to T/G mismatches. Cytosine methyltransferases methylate both strands of palindromic recognition sequences (CpG or CNG sequences in eukaryotes and CCWGG sequences in E. coli); consistent with their role in preventing mutations at 5-methylcytosines, the DNA repair systems show a strong preference for T/G mismatches which arise in methylase recognition sequences (31,32,46). E. coli initiates repair with a single-stranded endonuc...

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“…Furthermore, it has been shown that the chromatin occurrence of H2A.Bbd overlaps with regions containing acetylated H4 (10). Global acetylation of core histones also plays a very important role in the modulation of gene expression (51) and has been shown to change the NCP conformation (42) partially releasing the flanking DNA regions of the NCP (3, 52, 53). The salt‐dependent conformational change similarity between NCPs reconstituted with H2A.Bbd and native acetylated nucleosomes (Fig.…”

Section: Discussionmentioning

confidence: 99%

H2A.Bbd: a quickly evolving hypervariable mammalian histone that destabilizes nucleosomes in an acetylation‐independent way

Eirín‐López¹,

Ishibashi²,

Ausió³

2007

FASEB j.

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Molecular evolutionary analyses revealed that histone H2A.Bbd is a highly variable quickly evolving mammalian replacement histone variant, in striking contrast to all other histones. At the nucleotide level, this variability appears to be the result of a larger amount of nonsynonymous variation, which affects to a lesser extent, the structural domain of the protein comprising the histone fold. The resulting amino acid sequence diversity can be predicted to affect the internucleosomal and intranucleosomal histone interactions. Our phylogenetic analysis has allowed us to identify several of the residues involved. The biophysical characterization of nucleosomes reconstituted with recombinant mouse H2A.Bbd and their comparison to similar data obtained with human H2A.Bbd clearly support this notion. Despite the high interspecific amino acid sequence variability, all of the H2A.Bbd variants exert similar structural effects at the nucleosome level, which result in an unfolded highly unstable nucleoprotein complex. Such structure resembles that previously described for the highly dynamically acetylated nucleosomes associated with transcriptionally active regions of the genome. Nevertheless, the structure of nucleosome core particles reconstituted from H2A.Bbd is not affected by the presence of a hyperacetylated histone complement. This suggests that replacement by H2A.Bbd provides an alternative mechanism to unfold chromatin structure, possibly in euchromatic regions, in a way that is not dependent on acetylation.

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The role of histone variability in chromatin stability and folding

Cited by 14 publications

References 405 publications

Role of histone tails in chromatin folding revealed by a mesoscopic oligonucleosome model

Role of histone tails in chromatin folding revealed by a mesoscopic oligonucleosome model

MBD4-Mediated Glycosylase Activity on a Chromatin Template Is Enhanced by Acetylation

H2A.Bbd: a quickly evolving hypervariable mammalian histone that destabilizes nucleosomes in an acetylation‐independent way

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