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Transcription factors: from enhancer binding to developmental control

Key Points

  • Genetic studies during the past decades have revealed tightly regulated transcriptional networks that control robust developmental programs. However, this deterministic view of development contrasts with recent genomic studies that suggest that the multiple steps of transcription are by themselves rather leaky.

  • Although any single transcription factor (TF) can typically bind to thousands of sites throughout the genome, cis-regulatory activity at enhancers requires the concerted action of multiple binding events (which can be homotypic or heterotypic).

  • TFs bind to enhancers in a combinatorial manner, which is facilitated through direct and indirect cooperative mechanisms. The combinatorial nature of enhancer occupancy allows genes to be regulated in complex patterns in both space and time.

  • DNA and proteins can act together as a scaffold to cooperatively recruit TFs to enhancers.

  • Enhancers undergo progressive changes during development, in which their occupancy by TFs, and the position of nucleosomes with or without post-translational modifications, reflect their inactive, poised or active state.

  • Pioneer TFs recruit chromatin-remodelling factors to reposition nucleosomes, thus facilitating the occupancy of other TFs at subsequent developmental stages.

  • Enhancer priming can occur through many different mechanisms. For example, some TF binding events may serve as placeholders to prevent nucleosome repositioning.

  • Partially redundant enhancers can act to buffer changes in environmental conditions to ensure robust developmental progression.

  • Multiple elements regulating the same gene seem to assemble in a three-dimensional structure with the promoter, and can have synergistic or repressive influences on each other.

Abstract

Developmental progression is driven by specific spatiotemporal domains of gene expression, which give rise to stereotypically patterned embryos even in the presence of environmental and genetic variation. Views of how transcription factors regulate gene expression are changing owing to recent genome-wide studies of transcription factor binding and RNA expression. Such studies reveal patterns that, at first glance, seem to contrast with the robustness of the developmental processes they encode. Here, we review our current knowledge of transcription factor function from genomic and genetic studies and discuss how different strategies, including extensive cooperative regulation (both direct and indirect), progressive priming of regulatory elements, and the integration of activities from multiple enhancers, confer specificity and robustness to transcriptional regulation during development.

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Figure 1: Indirect mechanisms of transcription factor cooperativity.
Figure 2: Motif positioning (grammar) facilitates direct cooperativity between transcription factors.
Figure 3: Current models of enhancer activity.
Figure 4: Dynamic changes at enhancers during developmental progression.
Figure 5: Robustness through enhancer–enhancer interactions and redundancy.

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Acknowledgements

We are very grateful to J. Erceg, D. Harnett and P. Khoueiry for useful comments, with particular thanks to R. Zinzen and D. Garfield for some rephrasing. We apologize to all colleagues whose work was omitted due to space limitations; we unfortunately could not comment on all the interesting papers in the field. F.S. is supported by grants from the Human Frontier Science Program (HFSP), a European Commission grant (EC-FP7, grant Health 223210/CISSTEM). E.E.M.F. is supported by grants from the HFSP, the European Research Area for Systems Biology (ERASysBio) for the ModHeart project and the German Research Foundation (DFG; grant FU 750/1-1).

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FURTHER INFORMATION

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ENCODE and modENCODE

REDfly enhancer database

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Glossary

Core promoter

The region of a gene to which RNA polymerase II and the general transcription factors (GTFs) bind to initiate transcription. Core promoters span ~40 base pairs upstream and downstream of the transcription start site.

Silencers

DNA sequences to which repressor factors bind and mediate the silencing of promoters through interactions with the basal transcriptional machinery or enhancers.

Insulators

Chromatin elements that act as barriers against the influence of positive signals (from enhancers) or negative signals (from silencers and from heterochromatin).

Tethering elements

Cis-regulatory elements that contribute to directing a remote enhancer activity towards a specific gene among the surrounding genes. They are usually close to the promoter-proximal region of the target gene.

Bone morphogenetic protein

(BMP). A group of molecules of the transforming growth factor-α (TGFα) family that can induce bone formation and ventralize the vertebrate embryo. Decapentaplegic (DPP) is the fly homologue of the vertebrate BMPs.

Bicoid

A maternally deposited Drosophila melanogaster transcription factor that is localized at the anterior end of the embryo and forms a concentration gradient that decreases from the anterior to posterior. This transcription factor regulates transcription at different concentrations along its expression gradient, which is essential for establishing the segmentation of the early blastoderm embryo.

Mediator

The ~30-subunit co-activator complex that is necessary for successful transcription at class II promoters of metazoan genes. Mediator coordinates the signals between enhancers and the general transcription machinery through its interaction with RNA polymerase II and site-specific factors.

SAGA

A multiprotein complex involved in the regulation of transcription that possesses histone acetyltransferase and TATA-box-binding protein (TBP)-binding activities. The budding-yeast complex includes Gcn5, several proteins of the Spt and Ada families, and TBP-associated factors (TAFs); analogous complexes in other species have analogous compositions.

Nucleosome-depleted regions

(NDRs). DNA is usually wrapped around histone octamers, forming nucleosomes that contribute to genome compaction in the nucleus. The distribution of nucleosomes is variable and regulated, and some genomic regions, termed NDRs, show a lower density or absence of nucleosomes.

Chromatin immunoprecipitation

(ChIP). A technique for identifying potential regulatory sequences that are bound by a protein of interest. Covalently crosslinked DNA–chromatin extracts (complexes of DNA and protein) are isolated using antibodies that recognize specific DNA-binding proteins. In ChIP–chip, the ChIP step is followed by microarray analysis, whereas in ChIP–seq, it is followed by high-throughput sequencing.

Maternal-to-zygotic transition

(MZT). A period of embryonic development that coincides with the transcriptional activation of the zygotic (embryonic) genome. Most of the RNA and proteins that are present in the embryo before the MZT are provided by the mother, through maternal loading into the oocyte.

TAGteam motifs

A collection of related heptamer motifs (consensus sequence CAGGTAG) that are enriched in the vicinity of genes that are transcribed during the early blastoderm stages of Drosophila melanogaster embryogenesis; these motifs are recognized by the transcription factor Zelda.

Splanchnic mesoderm

The part of the mesoderm that associates with the endoderm and that will develop later into gut muscles and heart. In Drosophila melanogaster the splanchnic mesoderm is located dorsally, whereas in vertebrates it is ventral.

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Spitz, F., Furlong, E. Transcription factors: from enhancer binding to developmental control. Nat Rev Genet 13, 613–626 (2012). https://doi.org/10.1038/nrg3207

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