Nucleosomes can invade DNA territories occupied by their neighbors

Engeholm, Maik; Jager, Martijn de; Flaus, Andrew; Brenk, Ruth; Noort, John van; Owen-Hughes, Tom

doi:10.1038/nsmb.1551

Cited by 103 publications

(114 citation statements)

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“…KDM2A will never encounter an isolated mononucleosome in vivo, but instead extranucleosomal DNA will largely occur between nucleosomes on the chromatin polymer. Therefore, to examine whether KDM2A can bind to linker DNA between nucleosomes, we reconstituted dinucleosomes which consist of two 601 nucleosome positioning sequences separated by 48 bp of linker DNA (10). The only extranucleosomal DNA in this substrate exists between the positioned nucleosomes.…”

Section: Resultsmentioning

confidence: 99%

Recognition of CpG Island Chromatin by KDM2A Requires Direct and Specific Interaction with Linker DNA

Zhou

Blackledge

Farcas

et al. 2012

Molecular and Cellular Biology

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). Usually associated with the 5= end of genes, CpG islands are thought to impact gene expression. We previously demonstrated that the histone demethylase KDM2A is specifically recruited to CpG islands to define a unique chromatin architecture and highlight gene regulatory regions in large and complex mammalian genomes. This targeting relies on a zinc finger CXXC DNA binding domain (ZF-CXXC), but how this demethylase interfaces with CpG island chromatin in vivo remains unknown. Here we demonstrate, using defined chromatin templates in vitro and chromatin profiling in vivo, that nucleosomes are a major barrier to KDM2A binding and that CpG islands are directly interpreted by the ZF-CXXC domain through specific interaction with linker DNA. Furthermore, KDM2A appears to be constrained to CpG islands not only by their nonmethylated state but also by a combination of methylated DNA and nucleosome occlusion elsewhere in the genome. Our observations suggest that both DNA sequence and chromatin structure are defining factors in interpreting CpG island chromatin and translation of the CpG signal. More generally, these features of CpG island recognition suggest that chromatin structure and accessibility play a major role in defining how transcription factors recognize DNA and regulatory elements genome-wide. Genomic DNA information in eukaryotes is organized within the nucleus by packaging into repeated units called nucleosomes that consist of roughly 147 bp of DNA wrapped around an octamer of histone proteins. Packaging of DNA into nucleosomes permits compaction of the genome into the relatively small confines of the nucleus and can also significantly impact the function of DNA sequences with which it associates. For example, specific positioning of nucleosomes over gene regulatory elements can inhibit initiation of transcription (25-27) and nucleosomes in transcribed regions of genes can act as a barrier to transcriptional elongation (14,15,31,36). More recently it has become clear that modification of both DNA and histones can provide an additional layer of information that is specifically interpreted and alters the function of surrounding regions of the genome (21, 43). In the case of histone proteins, marking of N-terminal tails by a diverse complement of posttranslational modifications can lead to direct effects on chromatin packing (38) and specific nucleation of effector proteins that translate these modification signals into a functional outcome (1,8,22,43). The DNA component of the nucleosome can also be modified on the five position of the cytosine base by enzymatic addition of a methyl group which occurs mostly within the context of CpG dinucleotides (20). This methylated dinucleotide signal acts as a binding site for proteins containing a methyl-CpG binding domain (MBD) to create transcriptionally repressive chromatin states. Together these chromatin modification systems appear to have important roles in regulating the function of transcription and other nuclear processes.Since the majority of CpG dinucleotid...

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Section: Resultsmentioning

confidence: 99%

Recognition of CpG Island Chromatin by KDM2A Requires Direct and Specific Interaction with Linker DNA

Zhou

Blackledge

Farcas

et al. 2012

Molecular and Cellular Biology

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“…An interesting variation of the theme has been suggested, whereby a nucleosome is used as a "wedge" to destabilize an adjacent particle. If nucleosomes are moved to collide with one another, DNA may be peeled off one or both of them, yielding unconventional remodeling intermediates (Chaban et al 2008;Engeholm et al 2009;Dechassa et al 2010). This possibility is consistent with the fact that RSC engulfs the nucleosome to which it is bound (Fig.…”

Section: The Nuts and Bolts Of Nucleosome Remodelingmentioning

confidence: 99%

Nucleosome Remodeling and Epigenetics

Becker

Workman

2013

Cold Spring Harbor Perspectives in Biology

272

203

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“…Thus, distances between neighboring dyads are only approximately equal to measured distances between hydroxyl cut sites. Surprisingly, 38.7% of the distances between hydroxyl cleavage sites marking neighboring nucleosomes are less than 147 bp, indicating that nucleosomes frequently invade each other's territories (8). This is possible only if the DNA of at least one nucleosome in the pair is partially unwrapped (Fig.…”

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confidence: 99%

Ubiquitous nucleosome crowding in the yeast genome

Chereji¹,

Morozov

2014

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

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Nucleosomes may undergo a conformational change in which a stretch of DNA peels off the histone octamer surface as a result of thermal fluctuations or interactions with chromatin remodelers. Thus, neighboring nucleosomes may invade each other's territories by DNA unwrapping and translocation, or through initial assembly in partially wrapped states. A recent high-resolution map of distances between dyads of neighboring nucleosomes in Saccharomyces cerevisiae reveals that nucleosomes frequently overlap DNA territories of their neighbors. This conclusion is supported by lower-resolution maps of S. cerevisiae nucleosome lengths based on micrococcal nuclease digestion and paired-end sequencing. The average length of wrapped DNA follows a stereotypical pattern in genes and promoters, correlated with the well-known distribution of nucleosome occupancy: nucleosomal DNA tends to be shorter in promoters and longer in coding regions. To explain these observations, we have developed a biophysical model that uses a 10-11-bp periodic histone-DNA binding energy profile. The profile is based on the pattern of histone-DNA contacts in nucleosome crystal structures, as well as the idea of linker length discretization caused by higher-order chromatin structure. Our model is in agreement with the observed genome-wide distributions of interdyad distances, wrapped DNA lengths, and nucleosome occupancies. Furthermore, our approach explains in vitro measurements of the accessibility of nucleosome-covered target sites and nucleosome-induced cooperativity between DNA-binding factors. We rule out several alternative scenarios of histone-DNA interactions as inconsistent with the genomic data.partially unwrapped nucleosomes | DNA accessibility | gene regulation E ukaryotic genomes are organized into arrays of nucleosomes (1). Each nucleosome consists of a stretch of genomic DNA wrapped around a histone octamer core (2). The resulting complex of DNA with histones and other regulatory and structural proteins is called chromatin (1). Arrays of nucleosomes form 10-nm fibers that resemble beads on a string and, in turn, fold into higher-order structures (3). Depending on the organism and cell type, 75-90% of genomic DNA is packaged into nucleosomes (1). Because nucleosomal DNA is wrapped tightly around the histone octamer, its accessibility to various DNA-binding proteins, such as repair enzymes, transcription factors (TFs), polymerases, and recombinases, is suppressed. The question of how cellular functions are carried out on the chromatin template is one of the outstanding puzzles in eukaryotic biology.Recently, nucleosome dyad positions and distances between dyads of neighboring nucleosomes were mapped genome-wide with high precision in Saccharomyces cerevisiae (4). The in vivo map was obtained by chemical modification of engineered histones, DNA backbone cleavage by hydroxyl radicals, and highthroughput sequencing (Fig. 1A). Although more precise than methods based on micrococcal nuclease (MNase) digestion, whose accuracy is affected by MNase...

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Nucleosomes can invade DNA territories occupied by their neighbors

Cited by 103 publications

References 50 publications

Recognition of CpG Island Chromatin by KDM2A Requires Direct and Specific Interaction with Linker DNA

Recognition of CpG Island Chromatin by KDM2A Requires Direct and Specific Interaction with Linker DNA

Nucleosome Remodeling and Epigenetics

Ubiquitous nucleosome crowding in the yeast genome

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