Genome regulation occurs at the level of chromatin. The fundamental subunit of chromatin is the nucleo- some core particle, which consists of DNA wrapped around a protein octamer composed of the four core histones (H3, H4, H2A and H2B). At the basic organi- zational level, nucleosomes are arranged into ‘beads on a string’, which confers a 5- to 10-fold compaction of the genomic template. In addition, metazoan chro- matin contains linker histones, which bind in between nucleosomes and interact with core histones to form condensed fibres that are characterized by levels of compaction on the order of 50-fold and higher. The detailed organization of these higher-order structures is, however, less well understood 1 . Nucleosome pack- aging restricts protein binding and interferes with DNA-templated reactions. Local modulation of DNA accessibility thereby provides an opportunity to influ- ence the fundamental processes of transcription, rep- lication and repair. Indeed, chromatin structure is not static but subject to dynamic changes at every level of its hierarchy. Several determinants of DNA accessibility have been identified at the primary level of nucleosome arrays, and their interplay and function will be the main focus of this Review. In vitro studies show that nucleosomes display sub- stantial DNA sequence preferences 2,3 . In vivo, however, nucleosome localization is subject to contributions from combinations of thermal motion, competitive pro- tein binding and ATP-dependent remodelling, which cause sliding or temporary removal of the core histone octamer from the DNA 4,5 . Nucleosome mobility is fur- ther influenced by modifications to the histone octamer itself — such as exchange of histone variants or post- translational modifications. These can alter nucleosome properties or can serve to recruit chromatin-modifying proteins 6,7 . Replacement of canonical histones with vari- ant forms may alter interaction surfaces and the overall stability of nucleosomes 8 . Recent advances in microarray and massively paral- lel sequencing technologies have enabled the generation of genome-wide profiles of nucleosome occupancy, DNA accessibility and histone modification patterns at an unprecedented coverage and accuracy 9–12 . These profiles have been generated using methods such as chromatin immunoprecipitation followed by microarray (ChIP–chip), chromatin immunoprecipitation followed by sequencing (ChIP–seq) and deoxyribonuclease (DNase) or micro- coccal nuclease (MNase) digestion followed by sequenc- ing (DNase–seq and MNase–seq). These genomic maps are revealing the prevalence of stereotypic nucleosome arrangements and modifications, which define distinct chromatin architectures at cis-regulatory sequences, including enhancers and promoters. Moreover, these studies have uncovered cell-type-specific chromatin signatures that suggest a dynamic interplay between tissue-specific regulation by transcription factors and chromatin structure. The extent to which these changes in DNA accessibility are a cause or a consequence of productive transcription-factor binding remains a central question. *Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA. ‡ Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH‑4058 Basel, Switzerland. § University of Basel, Petersplatz 1, CH‑4003 Basel, Switzerland. Correspondence to O.B.  and D.S.  e‑mails: olibell@stanford.edu; dirk@fmi.ch doi:10.1038/nrg3017 Published online 12 July 2011 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. Determinants and dynamics of genome accessibility Oliver Bell*, Vijay K.Tiwari ‡ , Nicolas H. Thomä ‡ and Dirk Schübeler ‡§ 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. MODES OF TRANSCRIPTIONAL REGULATION REVIEWS 554 | AUGUST 2011 | VOLUME 12 www.nature.com/reviews/genetics © 2011 Macmillan Publishers Limited. All rights reserved