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Insights from genomic profiling of transcription factors

Key Points

  • Alterations in gene expression caused by the inappropriate level, structure or function of a transcription factor have been associated with a diverse set of human diseases. However, because most human transcription factors are essentially uncharacterized, the role of transcription factors in human health is currently greatly underappreciated.

  • Technological advances (such as chromatin immunoprecipitation followed by microarray or by sequencing) now allow transcription factor binding to be studied on a genome-wide scale.

  • Recent discoveries, such as the finding that most transcription factors bind to thousands of places in the genome, that binding sites are not just localized to proximal promoter regions and that some binding sites lack sequences similar to the consensus motif, have stimulated new ideas concerning long-range and combinatorial regulation.

  • Current genomic studies have not yet determined whether most human transcription factors bind alone or whether they cluster at hot spots in the genome. Answers to these questions require the genomic profiling of many more factors.

  • A crucial unanswered question is whether all binding events have a functional outcome (perhaps under some specific condition or in a specific cell type) or whether some transcription factor–genome interactions are simply irrelevant.

  • Issues that remain to be addressed include the design of comprehensive studies (for example, should all factors be studied in all cell types) and functional validation (for example, how can we determine the role of one specific binding site in its normal genomic context).

Abstract

A crucial question in the field of gene regulation is whether the location at which a transcription factor binds influences its effectiveness or the mechanism by which it regulates transcription. Comprehensive transcription factor binding maps are needed to address these issues, and genome-wide mapping is now possible thanks to the technological advances of ChIP–chip and ChIP–seq. This Review discusses how recent genomic profiling of transcription factors gives insight into how binding specificity is achieved and what features of chromatin influence the ability of transcription factors to interact with the genome. It also suggests future experiments that may further our understanding of the causes and consequences of transcription factor–genome interactions.

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Figure 1: Transcriptional regulation by promoters and enhancers.
Figure 2: Location analysis of transcription factors.
Figure 3: Models for recruitment of factors to sites that lack consensus motifs.
Figure 4: Incorrect interpretation of functional assays.
Figure 5: Communal action of a set of transcription factors.
Figure 6: Revised model for transcriptional regulation.

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Acknowledgements

The author thanks X. Xu, H. O'Geen and S. Frietze for providing data used in figure 2 and the members of the Farnham laboratory for their insights and discussions.

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Peggy J. Farnham is a member of the ENCODE Consortium and a member of an Epigenome Mapping Center, both of which are mentioned in the Review.

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Glossary

TATA box

A consensus sequence in promoters that is enriched in thymine and adenine residues and is important for the recruitment of the general transcriptional machinery at some promoters.

Initiator

An element with a consensus of YYANWYY (in which A is the transcription start site, N is any nucleotide, W is adenosine or thymine, and Y is a pyrimidine) that helps to recruit the general transcriptional machinery to promoters.

Initiation complex

The assembly of RNA polymerase and associated general factors that binds to the core promoter region.

Silencer

A DNA sequence capable of binding transcription factors that are termed repressors, which can negatively influence transcription by preventing recruitment of the general transcriptional machinery or by recruiting histone-modifying complexes that create repressive chromatin structures.

Transcription factor II D

A protein complex composed of several subunits, called TATA binding protein (TBP)-associated factors (TAFs), and the TBP. It is one of several complexes that make up the RNA polymerase II initiation machinery.

DamID

An alternative method to chromatin immunoprecipitation that uses a DNA-binding protein fused to a DNA methyltransferase. Adenine methylation of a region identifies it as being located near a binding site.

Reporter construct

A plasmid containing a promoter (and sometimes an enhancer) cloned upstream of a reporter gene (often simply called the reporter) that is introduced into cultured cells, animals or plants. Certain genes are chosen as reporters because their products can be easily or quantitatively assayed, or used as selectable markers.

CpG island

A sequence of at least 200 bp with a greater number of CpG sites than expected for its GC content. These regions are often GC rich and usually undermethylated. They correspond to the promoter regions of many mammalian genes.

Enhanceosome

A protein complex that binds to an enhancer region (which can be located upstream, downstream or in a gene); the transcription factors that compose the enhanceosome are thought to work cooperatively to stimulate transcription.

Heterochromatin

Chromatin that is characterized by very dense packing of DNA, which makes it less accessible to transcription factors. Certain regions of the genome, such as centromeres and telomeres, are always heterochromatinized (constitutive heterochromatin regions), whereas other regions are densely packed and repressed only in certain cells (facultative heterochromatin regions).

DNA methylation

An epigenetic DNA modification that can be added and removed without changing the original DNA sequence and that is characterized by the addition of a methyl group to the number 5 carbon of the cytosine pyrimidine ring.

Plant homeodomain finger

A 50–80 amino acid domain that contains a Cys4-His-Cys3 motif. It is found in more than 100 human proteins, several of which are involved in chromatin-mediated gene regulation.

Small interfering RNAs

Small antisense RNAs (20–25 nucleotides) that can be directly introduced into cells or be generated in cells from longer dsRNAs. They serve as guides for the cleavage of homologous mRNA in the RNA-induced silencing complex.

Transcription factory

A nuclear subcompartment that is rich in RNA polymerases and transcription factors, and in which there is clustering of active genes.

Interactome

A complete set of macromolecular interactions (physical and genetic). Current use of the word tends to refer to a comprehensive set of protein–protein interactions. However, the protein–DNA interactome (a network formed by transcription factors and their target genes) is also commonly studied.

Artificial zinc finger

Chimaeras of zinc finger domains — small protein domains that coordinate one or more zinc ions and that are commonly found in mammalian transcription factors — and an effector domain (for example, an activator, repressor, methylase or nuclease). Linking together six zinc fingers produces a target site of 18 bp, which is long enough to be unique in all known genomes.

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Farnham, P. Insights from genomic profiling of transcription factors. Nat Rev Genet 10, 605–616 (2009). https://doi.org/10.1038/nrg2636

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