Key Points
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Chromatin packaging of genomic DNA restricts accessibility for regulatory proteins but also provides an opportunity to regulate genomic function by modulating nucleosome position and local chromatin structure.
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Genome-wide profiles of nucleosome localization reveal defined chromatin architecture at functional regulatory sites, such as promoters and enhancers.
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Nucleosome localization at cis regulatory regions is influenced by several determinants, including DNA sequence, competitive transcription-factor binding and ATP-dependent nucleosome remodelling.
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Post-translational histone modifications and deposition of histone variants coincide with nucleosomal patterns at regulatory sites where they might specify and facilitate dynamic regulation of DNA accessibility.
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The initiation of replication occurs at origins of replication (ORIs). Positions of ORIs and their activity appear to depend on nucleosomal organization and modification.
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The DNA repair machinery has evolved strategies to sense and repair damage in the context of chromatin.
Abstract
In eukaryotes, all DNA-templated reactions occur in the context of chromatin. Nucleosome packaging inherently restricts DNA accessibility for regulatory proteins but also provides an opportunity to regulate DNA-based processes through modulating nucleosome positions and local chromatin structure. Recent advances in genome-scale methods are yielding increasingly detailed profiles of the genomic distribution of nucleosomes, their modifications and their modifiers. The picture now emerging is one in which the dynamic control of genome accessibility is governed by contributions from DNA sequence, ATP-dependent chromatin remodelling and nucleosome modifications. Here we discuss the interplay of these processes by reviewing our current understanding of how chromatin access contributes to the regulation of transcription, replication and repair.
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Acknowledgements
We thank S. Elgin, J. Crabtree and members of the Crabtree and Schübeler laboratories for their insightful comments on the manuscript. O.B. is supported by a Human Frontier Science Program fellowship. V.K.T. is supported by a Marie Curie International Incoming Fellowship (IIF) and a European Molecular Biology Organisation (EMBO) long-term postdoctoral fellowship. Research in the laboratory of D.S. and N.T. is supported by the Novartis Research Foundation. The laboratory of D.S. is supported by the European Union (Network of Excellence 'The Epigenome' LSHG-CT-2004-503433, LSHG-CT-2006-037415), the European Research Council (ERC-204264) and SystemsX.ch, the Swiss initiative in Systems Biology. Research in the laboratory of N.T. is supported by grants from the European Research Council (ERC-2010-StG 260481-MoBa-CS), Association of International Cancer Research (AICR10-0292), OncoSuisse (OCS-02365-02-2009) and the Swiss National Foundation (31003A_120205). We apologize to those colleagues whose work we could not mention owing to space limitations.
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Glossary
- Linker histones
-
Linker histones are not part of the nucleosomal core but, at least in the case of the linker histone H1, bind to DNA adjacent to the octamer.
- Thermal motion
-
In the context of nucleosomes, in vitro experiments under physiological salt conditions revealed that higher temperatures, especially at 37°C, promote short-range movement (that is, tens of base pairs) of nucleosomes in cis.
- Nucleosome occupancy
-
The probability that a genomic site is covered by a histone octamer; this is an average frequency measure in a cell population.
- Chromatin immunoprecipitation followed by microarray
-
(ChIP–chip). This is a technique that combines chromatin immunoprecipitation (ChIP) with detection on microarrays ('chip') to comprehensively investigate the distribution of a protein of interest. Protein–DNA complexes are immunoprecipitated and, after isolation, bound DNA sequences can be detected by hybridization to probes on a microarray chip.
- Chromatin immunoprecipitation followed by sequencing
-
(ChIP–seq). An advancement of chromatin immunoprecipitation followed by microarray (ChIP–chip), ChIP–seq combines ChIP with massively parallel DNA sequencing to identify binding sites of a protein of interest genome-wide.
- DNase I hypersensitive sites
-
Chromatin regions with frequent cleavage by DNase I. DNase I hypersensitivity generally reflects a local reduction in nucleosome occupancy.
- Nucleosome positioning
-
This can describe either the rotational or translational orientation of the DNA around the histone octamer. Rotational positioning describes the orientation of the DNA helix on the surface of the histone octamer. Translational nucleosome positioning relates to the specific 146 bp of genomic DNA covered by the histone octamer. A highly positioned nucleosome is one that covers the same sequence in most cells within a population.
- Bisulphite treatment
-
Treatment of DNA with bisulphite chemically converts unmethylated cytosines to uracil. As methylated cytosines are unaffected, the location of methylation can be identified by sequencing the bisulphite-treated DNA.
- Fluorescence in situ hybridization
-
(FISH). A technique that can be used to visualize the location of DNA sequences within the nucleus by using sequence-specific fluorescent probes and microscopy.
- Chromosome conformation capture
-
(3C). A technique used to study the spatial organization of chromosomal regions in vivo, based on the ligation of DNA elements that are in close physical proximity.
- Nucleosome-depleted regions
-
(NDRs). Sites of reduced nucleosome occupancy compared to immediate surrounding regions. NDRs are frequently located at the beginning and end of genes, harbour cis- regulatory binding sites and display sensitivity to DNase I and formaldehyde-assisted isolation of regulatory elements (FAIRE) detection.
- RSC
-
A multi-subunit chromatin remodelling complex that uses DNA-dependent ATP hydrolysis to catalyse nucleosome mobilization at active genes.
- Chromatin remodelling
-
Enzyme-assisted histone or nucleosome mobilization, which requires ATP hydrolysis. ATP-dependent chromatin remodelling influences local chromatin structure to facilitate or prevent protein accessibility, which is required to initiate DNA-templated reactions.
- FACT
-
Stands for 'facilitates chromatin transcription' and is a chromatin-specific histone chaperone that is required for transcriptional elongation through chromatin templates.
- PHD domains
-
Derived from the name 'plant homeodomain', these protein domains were initially discovered as a Cys4-His-Cys3 motif in the homeodomain protein HAT3 in Arabidopsis thaliana. They are present in many proteins, several of which are nuclear and involved in chromatin-mediated gene regulation.
- 30 nm fibres
-
An array of nucleosomes (often called 'beads on a string') wraps into a more condensed fibre, which has a diameter of 30 nm. A simple 30 nm fibre has been reconstituted in vitro, but its actual composition in vivo remains unclear.
- Constitutive heterochromatin
-
Genomic regions, predominantly at centromeres and telomeres, which remain condensed throughout the cell cycle. These often consist of highly condensed, repetitive DNA and are largely transcriptionally silent.
- Polycomb group proteins
-
An evolutionarily conserved set of proteins that regulate the temporal and spatial expression pattern of key developmental genes through modulation of chromatin structure.
- Origin-recognition complex
-
A multi-subunit protein complex that binds to origins of replication and that is essential for initiation of replication.
- Nucleotide excision repair
-
A versatile repair pathway that is involved in the removal of the most bulky DNA lesions, such as UV-induced thymine dimers and 6–4 photoproducts. If left unrepaired, these lesions stall transcription and can only be repaired through potentially error-prone translesion polymerases. Mutations in this pathway result in premature ageing syndromes, as well as cancer predisposition.
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Bell, O., Tiwari, V., Thomä, N. et al. Determinants and dynamics of genome accessibility. Nat Rev Genet 12, 554–564 (2011). https://doi.org/10.1038/nrg3017
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DOI: https://doi.org/10.1038/nrg3017
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