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Nucleosome positioning and gene regulation: advances through genomics

Key Points

  • Eukaryotes possess promoter and termination regions that are largely nucleosome free.

  • Nucleosomes are positioned at canonical distances from the transcription start site (TSS).

  • In Saccharomyces cerevisiae, the TSS resides at the nucleosome border, suggesting that the transcription machinery must contend with the +1 nucleosome before initiation. In metazoans, the TSS resides in the NFR, suggesting that RNA polymerase II contends with the first nucleosome after initiation.

  • Genomic DNA sequences, such as periodic AA and TT dinucleotides, promote nucleosome formation, whereas poly (dA:dT) tracks promote nucleosome-free regions (NFRs). These sequences can be spread out and difficult to discern, but pave a continuous thermodynamic landscape of nucleosome occupancy across the genome.

  • Nucleosomes at the 5′ end of genes are enriched with histone variants (H2A.Z and H3.3) and post-translational modifications (for example, H3Ac, H4Ac and H3K4me3), some of which might make nucleosomes more dynamic.

  • A speculative model is proposed in which the TSS at many genes is directed in part by the first nucleosome downstream of the promoter NFR.

  • Chromatin remodelling complexes slide, remodel and evict nucleosomes to regulate DNA access and, ultimately, gene expression.

Abstract

Knowing the precise locations of nucleosomes in a genome is key to understanding how genes are regulated. Recent 'next generation' ChIP–chip and ChIP–Seq technologies have accelerated our understanding of the basic principles of chromatin organization. Here we discuss what high-resolution genome-wide maps of nucleosome positions have taught us about how nucleosome positioning demarcates promoter regions and transcriptional start sites, and how the composition and structure of promoter nucleosomes facilitate or inhibit transcription. A detailed picture is starting to emerge of how diverse factors, including underlying DNA sequences and chromatin remodelling complexes, influence nucleosome positioning.

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Figure 1: Nucleosome structure.
Figure 2: Nucleosomal landscape of yeast genes.
Figure 3: Phasing information and rotational setting.
Figure 4: Sequence-based packing versus statistical packing.
Figure 5: Mechanistic differences between transcription initiation in budding yeast and metazoans.
Figure 6: Mechanisms that allow DNA accessibility.

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Acknowledgements

We thank S. Tan for providing the image for Fig. 1a. Support from National Institutes of Health grant HG004160 is gratefully acknowledged.

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Correspondence to B. Franklin Pugh.

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Glossary

Chromatin remodelling complex

An ATP-dependent enzyme that is catalysed by different types of ATPase to alter nucleosome structure. The net effect of all chromatin remodelling enzymes is to modify nucleosome position or to increase accessibility of nucleosomal DNA.

Nucleosome-free region

(NFR). An 140 bp region lacking nucleosomes that is found at the beginning and end of genes. Many regions might not be completely nucleosome free, but are depleted of nucleosomes compared with the surrounding region. Certain environmental conditions can cause nucleosomes to occupy an NFR; for example, when genes are repressed.

ChIP–chip

A method for detecting the location of proteins throughout a genome using chromatin-immunoprecipitation followed by microarray analysis.

ChIP–Seq

A method for detecting the location of proteins throughout a genome using chromatin-immunoprecipitation followed by high-throughput DNA sequencing.

Phasing

The distribution of nucleosomes around a particular coordinate in a population of cells.

Rotational setting

The local orientation of the DNA helix on the histone surface.

Translational setting

The nucleosomal DNA midpoint position relative to a chromosomal locus.

Linker DNA

A short length of DNA located between nucleosomes. Long linker DNA can be considered to be a nucleosome-free region (NFR) — the DNA length cut-off for the two classes is arbitrary. However, NFRs tend to be sites of RNA and DNA polymerase loading and unloading.

Pre-initiation complex

(PIC). This assembly is found at the promoter and before the complex has initiated transcription. It includes the general transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH), the mediator, the RNA polymerase II complex, and activator or co-activator proteins (including SAGA).

Support vector machine classifier

A widely used method of classifying training data (for example, nucleosomal compared with non-nucleosomal genomic DNA), which can then be used to make predictions de novo.

Hidden Markov modelling

A method of identifying unknown or hidden states (for example, nucleosome positions) from observable states (for example, measured nucleosome positions).

Cryptic transcription

A low level of presumably unregulated transcription that originates from nucleosome-free regions. The transcripts are usually rapidly degraded.

SAGA complex

A multisubunit multifunctional complex that delivers TATA-binding protein (TBP) to promoters (by Spt3 and Spt8 subunits), acetylates nucleosomes (by the Gcn5 subunit) and is associated with activities that remodel (by Chd1) and deubiquitylate (by Ubp8) nucleosomes.

TFIID

A multisubunit general transcription factor composed of TATA-binding protein (TBP) and 15 other subunits (TBP-associated factors).

Core promoter element

A widely used DNA sequence element that helps position the transcription initiation complex, and is typically located within 60 bp of the transcription start site.

General transcription factor

A protein that is widely considered to be required to set up a transcription initiation complex at all promoters (examples include TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH).

TATA-binding protein

(TBP). This protein is important for assembling the transcription initiation complex.

Initiator element

(INR element). A DNA sequence that specifies the transcription start site (consensus abbreviations include: K = G or T; Y = C or T; W = A or T; N = G, A, T or C).

Histone chaperone

A member of a class of proteins that help to deposit histones onto DNA, but are not components of nucleosomes.

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Jiang, C., Pugh, B. Nucleosome positioning and gene regulation: advances through genomics. Nat Rev Genet 10, 161–172 (2009). https://doi.org/10.1038/nrg2522

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