Chromatin Compaction at the Mononucleosome Level

Tóth, Katalin; Brun, Nathalie; Langowski, Jörg

doi:10.1021/bi052110u

Cited by 65 publications

(92 citation statements)

References 39 publications

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“…5A). Two distinct conformations for the linker DNAs are obtained: Crossed conformations where linker DNAs intersect after emerging from the nucleosome, and open conformations where they diverge from each other, also consistent with experiments (44,45). The 2 types of linker DNA trajectories are better assessed from their positional distribution plots (projected onto the nucleosomal and dyad planes; Fig.…”

Section: Internucleosomal Interactions Mapping By Emanicsupporting

confidence: 76%

Evidence for heteromorphic chromatin fibers from analysis of nucleosome interactions

Grigoryev

Arya

Correll

et al. 2009

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

245

358

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The architecture of the chromatin fiber, which determines DNA accessibility for transcription and other template-directed biological processes, remains unknown. Here we investigate the internal organization of the 30-nm chromatin fiber, combining Monte Carlo simulations of nucleosome chain folding with EM-assisted nucleosome interaction capture (EMANIC). We show that at physiological concentrations of monovalent ions, linker histones lead to a tight 2-start zigzag dominated by interactions between alternate nucleosomes (i ؎ 2) and sealed by histone N-tails. Divalent ions further compact the fiber by promoting bending in some linker DNAs and hence raising sequential nucleosome interactions (i ؎ 1). Remarkably, both straight and bent linker DNA conformations are retained in the fully compact chromatin fiber as inferred from both EMANIC and modeling. This conformational variability is energetically favorable as it helps accommodate DNA crossings within the fiber axis. Our results thus show that the 2-start zigzag topology and the type of linker DNA bending that defines solenoid models may be simultaneously present in a structurally heteromorphic chromatin fiber with uniform 30 nm diameter. Our data also suggest that dynamic linker DNA bending by linker histones and divalent cations in vivo may mediate the transition between tight nucleosome packing within discrete 30-nm fibers and self-associated higher-order chromosomal forms.chromatin structure ͉ electron microscopy ͉ mesoscopic modeling ͉ Monte Carlo simulations ͉ linker histone T he DNA in eukaryotic chromatin is packed and functionally regulated by histones and nonhistone architectural proteins (1). The primary packing level is represented by an array of repeating units, the nucleosomes, where the DNA is wound around histone octamers (2). Further compaction is achieved through a hierarchy of folding levels, including the 30-nm chromatin fiber (secondary level) and more compact and self-associating tertiary and quaternary forms whose structures are unknown (3-6). Because DNA conformation in chromatin and nucleosome packing are intimately connected to DNA/protein recognition and gene regulation, there has been intense interest in understanding chromatin structure, energetics, and dynamics. Some experimental studies have suggested that nucleosomal arrays fold in a zigzag arrangement with relatively straight linkers and a 2-start nucleosome interaction pattern that brings each nucleosome in proximity to its second nearest neighbor (7-10) consistent with chromatin fibers observed in situ (11). Other evidence suggests that chromatin condensed with linker histones and divalent cations such as Mg 2ϩ can form either zigzag structures with various nucleosome topologies (12, 13) or solenoid-like arrangements. The latter class of structures has bent DNA linkers and predominant interactions between either nearest neighbor nucleosomes (14, 15) and/or between every fifth or sixth nucleosome along the chain (16,17).The picture has became more complex recently with our heighte...

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Section: Internucleosomal Interactions Mapping By Emanicsupporting

confidence: 76%

Evidence for heteromorphic chromatin fibers from analysis of nucleosome interactions

Grigoryev

Arya

Correll

et al. 2009

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

245

358

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“…The latter assertion is supported by the FRET measurements of DNA labeled nucleosomes (44,45), which reveal distinct structural changes on the mononucleosomal level that are driven solely by H4 acetylation. Furthermore, these FRETexperiments indicate that H4 acetylation results in tightening of the free DNA ends coming out of the nucleosome (44,45). The latter result may be potentially consistent with the idea of stronger binding of AC H4 tail to its own nucleosomal DNA, which is the main suggestion of the current work.…”

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confidence: 69%

“…The stronger interaction of the AC H4 with the DNA is expected to have a noticeable structural impact on the local internucleosomal configurations, which would then propagate down further by ultimately changing the chromatin architecture on a much larger scale (12). The latter assertion is supported by the FRET measurements of DNA labeled nucleosomes (44,45), which reveal distinct structural changes on the mononucleosomal level that are driven solely by H4 acetylation. Furthermore, these FRETexperiments indicate that H4 acetylation results in tightening of the free DNA ends coming out of the nucleosome (44,45).…”

mentioning

confidence: 87%

“…The unique role of the H4 histone tail in maintaining the chromatin architectural organization has been established by sedimentation experiments (30), which showed that, from all the tails, only the absence of H4, or equivalently its acetylation, can cause an irreversible disruption of the chromatin fiber. One commonly accepted explanation states (14) that all of the WT core histone tail domains have well-pronounced preference to bind the linker DNA-the short segment that joins two adjacent nucleosomes (44,46). Coarsegrained molecular simulations also seem to stress the importance of the so-called "tail bridging" effect in increasing the attraction between the nucleosome cores (47).…”

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confidence: 99%

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Regulation of the H4 tail binding and folding landscapes via Lys-16 acetylation

Potoyan

Papoian

2012

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

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Intrinsically disordered proteins (IDP) are a broad class of proteins with relatively flat energy landscapes showing a high level of functional promiscuity, which are frequently regulated through posttranslational covalent modifications. Histone tails, which are the terminal segments of the histone proteins, are prominent IDPs that are implicated in a variety of signaling processes, which control chromatin organization and dynamics. Although a large body of work has been done on elucidating the roles of posttranslational modifications in functional regulation of IDPs, molecular mechanisms behind the observed behaviors are not fully understood. Using extensive atomistic molecular dynamics simulations, we found in this work that H4 tail mono-acetylation at LYS-16, which is a key covalent modification, induces a significant reorganization of the tail's conformational landscape, inducing partial ordering and enhancing the propensity for alpha-helical segments. Furthermore, our calculations of the potentials of mean force between the H4 tail and a DNA fragment indicate that contrary to the expectations based on simple electrostatic reasoning, the Lys-16 monoacetylated H4 tail binds to DNA stronger than the unacetylated protein. Based on these results, we propose a molecular mechanism for the way Lys-16 acetylation might lead to experimentally observed disruption of compact chromatin fibers.histone tails | atomistic simulations | polyelectrolytes

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“…Fortunately, unlike the recently discovered Rsc4p acetylation, histone acetylation has been the focus of intense study for many decades. To date, histone H3 acetylation has been proposed to function in two, non-mutually exclusive manners: to act as a molecular "tag" for the recruitment of chromatin-modifying complexes (42) and to directly alter chromatin structure by weakening histone-DNA contacts (10,39). We hypothesized that if the loss of H3 acetylation is disrupting the binding of a chromatin-modifying complex to the H3 tail, then mutation of the acetylatable lysines to glutamine should recapitulate the phenotypes of arginine substitutions and be lethal in a rsc4K25A mutant.…”

Section: Downloaded Frommentioning

confidence: 99%

Acetylation of Rsc4p by Gcn5p Is Essential in the Absence of Histone H3 Acetylation

Choi

Grimes

Rowe

et al. 2008

Molecular and Cellular Biology

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Rsc4p, a subunit of the RSC chromatin-remodeling complex, is acetylated at lysine 25 by Gcn5p, a wellcharacterized histone acetyltransferase (HAT). Mutation of lysine 25 does not result in a significant growth defect, and therefore whether this modification is important for the function of the essential RSC complex was unknown. In a search to uncover the molecular basis for the lethality resulting from loss of multiple histone H3-specific HATs, we determined that loss of Rsc4p acetylation is lethal in strains lacking histone H3 acetylation. Phenotype comparison of mutants with arginine and glutamine substitutions of acetylatable lysines within the histone H3 tail suggests that it is a failure to neutralize the charge of the H3 tail that is lethal in strains lacking Rsc4p acetylation. We also demonstrate that Rsc4p acetylation does not require any of the known Gcn5p-dependent HAT complexes and thus represents a truly novel function for Gcn5p. These results demonstrate for the first time the vital and yet redundant functions of histone H3 and Rsc4p acetylation in maintaining cell viability.Posttranslational modifications can augment protein function extending the diversity of proteins produced by the cell. For example, many thousands of proteins in a typical eukaryotic cell are modified by the covalent addition of a phosphate group (22), which can serve to either directly alter protein structure or mediate protein-protein interactions. Another well-studied modification is protein acetylation. Amino-terminal acetylation is one of the most common protein modifications in eukaryotes, occurring on ca. 85% of proteins. In addition, the acetylation of the epsilon-amino group of internal lysines occurs on ␣-tubulin, high-mobility group proteins, transcription factors, nuclear import factors, and histones (28).Histones H2A, H2B, H3, and H4 are the best-characterized substrates for posttranslational acetylation of internal lysines, with the majority of histone acetylation occurring on the unstructured amino-terminal "tails" of these proteins. These modifications are proposed to have two functions: to directly alter chromatin structure by weakening histone-DNA, as well as internucleosome interactions (1,2,11,33,34), and to act as a "molecular dock" for recruitment of factors that modify chromatin structure (42). Histone acetylation is catalyzed by histone acetyltransferases (HATs), which are comprised of a catalytic subunit complexed with accessory proteins that serve to either target or potentiate HAT activity. The best-studied catalytic subunit is Gcn5p, a component of multiple histone H3-specific HAT complexes in Saccharomyces cerevisiae. These complexes are responsible for acetylation of lysines 9, 14, 18, 23, 27, and 36 of histone H3 (14, 26, 37). All Gcn5p-dependent HAT complexes share the accessory proteins Ada2p and Ada3p, and several studies have demonstrated that ADA2 and ADA3 are essential for both the nucleosomal HAT activity of Gcn5p and its incorporation into HAT complexes (5, 7, 13). Indeed, the majority of p...

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Chromatin Compaction at the Mononucleosome Level

Cited by 65 publications

References 39 publications

Evidence for heteromorphic chromatin fibers from analysis of nucleosome interactions

Evidence for heteromorphic chromatin fibers from analysis of nucleosome interactions

Regulation of the H4 tail binding and folding landscapes via Lys-16 acetylation

Acetylation of Rsc4p by Gcn5p Is Essential in the Absence of Histone H3 Acetylation

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