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The effect of linker histone's nucleosome binding affinity on chromatin unfolding mechanisms.

ABSTRACT: Eukaryotic gene activation requires selective unfolding of the chromatin fiber to access the DNA for processes such as DNA transcription, replication, and repair. Mutation/modification experiments of linker histone (LH) H1 suggest the importance of dynamic mechanisms for LH binding/dissociation, but the effects on chromatin's unfolding pathway remain unclear. Here we investigate the stretching response of chromatin fibers by mesoscale modeling to complement single-molecule experiments, and present various unfolding mechanisms for fibers with different nucleosome repeat lengths (NRLs) with/without LH that are fixed to their cores or bind/unbind dynamically with different affinities. Fiber softening occurs for long compared to short NRL (due to facile stacking rearrangements), dynamic compared to static LH/core binding as well as slow rather than fast dynamic LH rebinding (due to DNA stem destabilization), and low compared to high LH concentration (due to DNA stem inhibition). Heterogeneous superbead constructs--nucleosome clusters interspersed with extended fiber regions--emerge during unfolding of medium-NRL fibers and may be related to those observed experimentally. Our work suggests that fast and slow LH binding pools, present simultaneously in vivo, might act cooperatively to yield controlled fiber unfolding at low forces. Medium-NRL fibers with multiple dynamic LH pools offer both flexibility and selective DNA exposure, and may be evolutionarily suitable to regulate chromatin architecture and gene expression.

SUBMITTER: Collepardo-Guevara R

PROVIDER: S-EPMC3183807 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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The effect of linker histone's nucleosome binding affinity on chromatin unfolding mechanisms.

Collepardo-Guevara Rosana R Schlick Tamar T

Biophysical journal 20111001 7

Eukaryotic gene activation requires selective unfolding of the chromatin fiber to access the DNA for processes such as DNA transcription, replication, and repair. Mutation/modification experiments of linker histone (LH) H1 suggest the importance of dynamic mechanisms for LH binding/dissociation, but the effects on chromatin's unfolding pathway remain unclear. Here we investigate the stretching response of chromatin fibers by mesoscale modeling to complement single-molecule experiments, and prese ...[more]

PMID: 21961593

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Project description:The linker histone (LH), an auxiliary protein that can bind to chromatin and interact with the linker DNA to form stem motifs, is a key element of chromatin compaction. By affecting the chromatin condensation level, it also plays an active role in gene expression. However, the presence and variable concentration of LH in chromatin fibers with different DNA linker lengths indicate that its folding and condensation are highly adaptable and dependent on the immediate nucleosome environment. Recent experimental studies revealed that the behavior of LH in mononucleosomes markedly differs from that in small nucleosome arrays, but the associated mechanism is unknown. Here we report a structural analysis of the behavior of LH in mononucleosomes and oligonucleosomes (2-6 nucleosomes) using mesoscale chromatin simulations. We show that the adapted stem configuration heavily depends on the strength of electrostatic interactions between LH and its parental DNA linkers, and that those interactions tend to be asymmetric in small oligonucleosome systems. Namely, LH in oligonucleosomes dominantly interacts with one DNA linker only, as opposed to mononucleosomes where LH has similar interactions with both linkers and forms a highly stable nucleosome stem. Although we show that the LH condensation depends sensitively on the electrostatic interactions with entering and exiting DNA linkers, other interactions, especially by nonparental cores and nonparental linkers, modulate the structural condensation by softening LH and thus making oligonucleosomes more flexible, in comparison to to mono- and dinucleosomes. We also find that the overall LH/chromatin interactions sensitively depend on the linker length because the linker length determines the maximal nucleosome stem length. For mononucleosomes with DNA linkers shorter than LH, LH condenses fully, while for DNA linkers comparable or longer than LH, the LH extension in mononucleosomes strongly follows the length of DNA linkers, unhampered by neighboring linker histones. Thus, LH is more condensed for mononucleosomes with short linkers, compared to oligonucleosomes, and its orientation is variable and highly environment-dependent. More generally, the work underscores the agility of LH whose folding dynamics critically controls genomic packaging and gene expression.

Dataset Information

The effect of linker histone's nucleosome binding affinity on chromatin unfolding mechanisms.

Publications

The effect of linker histone's nucleosome binding affinity on chromatin unfolding mechanisms.

Similar Datasets

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