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  • Review Article
  • Published:

From DNA sequence to transcriptional behaviour: a quantitative approach

Nature Reviews Genetics volume 10, pages 443–456 (2009)Cite this article

Key Points

  • This Review presents a unifying quantitative and conceptual framework for translating DNA sequences into transcriptional behaviours.

  • Each DNA-binding molecule has specific DNA sequence preferences (affinities) and, thus, every regulatory sequence defines a unique affinity landscape for each molecule.

  • At given concentrations of DNA-binding molecules, the unique affinity landscape of a regulatory sequence dictates a distinct distribution of molecule-binding configurations and, consequently, a distinct transcriptional output.

  • Accurate models of the DNA sequence preferences of nucleosomes and of many transcription factors are now available.

  • The intrinsic DNA sequence preferences of nucleosomes are major determinants of nucleosome organization in vivo, and partly account for the depletion of nucleosomes around the starts and ends of genes.

  • Nucleosome depletion around transcription factor-binding sites is partly encoded in the nucleosome affinity landscape of the genome and might assist in directing factors to their appropriate genomic sites.

  • Differences in the intrinsic nucleosome affinity landscapes in which factor-binding sites are embedded might allow the same factor to regulate its different targets with different activation dynamics.

  • Two factors that have adjacent binding sites can show indirect binding cooperativity through competition with nucleosomes, allowing some factors to function as activators on some regulatory sequences but as inhibitors on others.

  • The affinity landscape of a regulatory sequence dictates when factors must compete with nucleosomes for access to the DNA, partly explaining the differential requirement for chromatin remodellers at different loci.

  • DNA sequence changes that directly alter the nucleosome affinity landscape of a regulatory sequence might help to drive phenotypic diversity across evolution.

  • Variability in cell-to-cell expression and in DNA replication can be partly explained in terms of the affinity landscape of a DNA sequence for transcription factors and nucleosomes.

Abstract

Complex transcriptional behaviours are encoded in the DNA sequences of gene regulatory regions. Advances in our understanding of these behaviours have been recently gained through quantitative models that describe how molecules such as transcription factors and nucleosomes interact with genomic sequences. An emerging view is that every regulatory sequence is associated with a unique binding affinity landscape for each molecule and, consequently, with a unique set of molecule-binding configurations and transcriptional outputs. We present a quantitative framework based on existing methods that unifies these ideas. This framework explains many experimental observations regarding the binding patterns of factors and nucleosomes and the dynamics of transcriptional activation. It can also be used to model more complex phenomena such as transcriptional noise and the evolution of transcriptional regulation.

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Figure 1: Overview of quantitative models for computing expression from DNA sequences.
Figure 2: Main determinants of in vivo nucleosome organization.
Figure 3: Reading gene expression dynamics from DNA sequence.
Figure 4: Distinct modes of transcriptional regulation encoded by DNA sequence.
Figure 5: Explaining transcriptional noise from DNA sequence.

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Acknowledgements

We thank the members of our laboratories for discussions and critical comments on the manuscript. E.S. acknowledges research support from the National Institutes of Health and the European Research Council and J.W. acknowledges research support from the National Institutes of Health. E.S. is the incumbent of the Soretta and Henry Shapiro career development chair.

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Authors and Affiliations

  1. Department of Computer Science and Applied Mathematics and Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel

    Eran Segal

  2. Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, 2205 Tech Drive, Evanston, 60208-3500, Illinois, USA

    Jonathan Widom

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DATABASES

Saccharomyces Genome Database

Abf1

Pho4

Reb1

FURTHER INFORMATION

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Nature Reviews Genetics Series on Modelling

Glossary

Nucleosome

The basic unit of chromatin, which contains 147 bp of DNA wrapped around a histone protein octamer.

Binding configuration

A particular arrangement of molecules along a DNA sequence, which includes specification of the precise position and orientation (or DNA strand) at which each molecule is bound.

Transcriptional noise

The variability in the transcription rate (or in steady state mRNA levels) of genes across different cells from an isogenic cell population grown in the same conditions.

Chromatin remodeller

A protein or protein complex that has the capacity to alter the structure of chromatin. Some remodellers require ATP hydrolysis for their activity.

Footprinting

A method for detecting protein–DNA interactions by using an enzyme to cut DNA, followed by analysis of the resulting cleavage pattern. The method is based on the fact that a protein bound to DNA protects that DNA from enzymatic cleavage.

Gel-shift analysis

A technique that uses native gel electrophoresis to determine whether, and how tightly, a protein of interest can bind a given DNA sequence.

Southwestern blotting

A method that involves identifying DNA-binding proteins after SDS–PAGE and transfer to a membrane using their ability to bind to specific oligonucleotide probes.

SELEX

(Systematic evolution of ligands by exponential enrichment). A combinatorial technique for producing DNAs that bind specifically and with high affinity to a DNA-binding protein of interest.

ChIP–chip

A technique (also known as ChIP-on-chip) that combines chromatin immunoprecipitation (ChIP) with microarray technology (chip). It is a high-throughput method for identifying, on a genome-wide scale, DNA regions that are bound in vivo by a target protein of interest.

ChIP–seq

A similar technique to ChIP–chip, but the resulting interactions are read out by high-throughput parallel sequencing and not by microarrays as in ChIP–chip.

Protein-binding microarray

A method that allows the high-throughput characterization of the in vitro DNA-binding site sequence specificities of transcription factors. In this approach, a DNA-binding protein of interest is expressed, purified and then bound directly to a dsDNA microarray that contains a large number of different potential DNA-binding sites.

Microfluidic platform

A high-throughput platform for measuring protein–DNA affinities on the basis of mechanically induced trapping of molecular interactions.

DNA looping

A conformation of a dsDNA sequence in which two regions of the DNA that are separated along the DNA in one dimension are brought close together in three-dimensional space.

Legal configuration

An arrangement of molecules along a DNA sequence in which there is no steric overlap between any two molecules on the DNA.

TATA sequence

A DNA sequence with a core sequence of 5′–TATA–3′ found in the promoter region of many genes. It is typically bound by a corresponding TATA-binding protein during the process of recruiting RNA polymerase to a promoter.

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Segal, E., Widom, J. From DNA sequence to transcriptional behaviour: a quantitative approach. Nat Rev Genet 10, 443–456 (2009). https://doi.org/10.1038/nrg2591

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