Skip to main content
SpringerLink
Log in

The grammar of transcriptional regulation

  • Review Paper
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Eukaryotes employ combinatorial strategies to generate a variety of expression patterns from a relatively small set of regulatory DNA elements. As in any other language, deciphering the mapping between DNA and expression requires an understanding of the set of rules that govern basic principles in transcriptional regulation, the functional elements involved, and the ways in which they combine to orchestrate a transcriptional output. Here, we review the current understanding of various grammatical rules, including the effect on expression of the number of transcription factor binding sites, their location, orientation, affinity and activity; co-association with different factors; and intrinsic nucleosome organization. We review different methods that are used to study the grammar of transcription regulation, highlight gaps in current understanding, and discuss how recent technological advances may be utilized to bridge them.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Arnold CD et al (2013) Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339:1074–1077

    Article  CAS  PubMed  Google Scholar 

  • Badis G et al (2009) Diversity and complexity in DNA recognition by transcription factors. Science 324:1720–1723

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bakiri L, Matsuo K, Wisniewska M, Wagner EF, Yaniv M (2002) Promoter specificity and biological activity of tethered AP-1 dimers. Mol Cell Biol 22:4952–4964

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Beer MA, Tavazoie S (2004) Predicting gene expression from sequence. Cell 117:185–198

    Article  CAS  PubMed  Google Scholar 

  • Beisel C, Paro R (2011) Silencing chromatin: comparing modes and mechanisms. Nat Rev Genet 12:123–135

    Article  CAS  PubMed  Google Scholar 

  • Berger MF et al (2008) Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 133:1266–1276

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Blanco J, Girard F, Kamachi Y, Kondoh H, Gehring WJ (2005) Functional analysis of the chicken delta1-crystallin enhancer activity in Drosophila reveals remarkable evolutionary conservation between chicken and fly. Development 132:1895–1905

    Article  CAS  PubMed  Google Scholar 

  • Burz DS, Rivera-Pomar R, Jackle H, Hanes SD (1998) Cooperative DNA-binding by Bicoid provides a mechanism for threshold-dependent gene activation in the Drosophila embryo. EMBO J 17:5998–6009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chiang DY, Nix DA, Shultzaberger RK, Gasch AP, Eisen MB (2006) Flexible promoter architecture requirements for coactivator recruitment. BMC Mol Biol 7:16

    Article  PubMed Central  PubMed  Google Scholar 

  • Coleman RA, Pugh BF (1995) Evidence for functional binding and stable sliding of the TATA binding protein on nonspecific DNA. J Biol Chem 270:13850–13859

    Article  CAS  PubMed  Google Scholar 

  • Cox RS 3rd, Surette MG, Elowitz MB (2007) Programming gene expression with combinatorial promoters. Mol Syst Biol 3:145

    PubMed Central  PubMed  Google Scholar 

  • Crawford GE et al (2006) Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS). Genome Res 16:123–131

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25:1010–1022

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dostie J, Dekker J (2007) Mapping networks of physical interactions between genomic elements using 5C technology. Nat Protoc 2:988–1002

    Article  CAS  PubMed  Google Scholar 

  • Dunham I et al (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74

    Article  CAS  PubMed  Google Scholar 

  • Field Y et al (2008) Distinct modes of regulation by chromatin encoded through nucleosome positioning signals. PLoS Comput Biol 4:e1000216

    Article  PubMed Central  PubMed  Google Scholar 

  • FitzGerald PC, Shlyakhtenko A, Mir AA, Vinson C (2004) Clustering of DNA sequences in human promoters. Genome Res 14:1562–1574

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gaulton KJ et al (2010) A map of open chromatin in human pancreatic islets. Nat Genet 42:255–259

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gencheva M et al (2006) In Vitro and in Vivo nucleosome positioning on the ovine beta-lactoglobulin gene are related. J Mol Biol 361:216–230

    Article  CAS  PubMed  Google Scholar 

  • Gerstein MB et al (2012) Architecture of the human regulatory network derived from ENCODE data. Nature 489:91–100

    Article  CAS  PubMed  Google Scholar 

  • Gertz J, Siggia ED, Cohen BA (2009) Analysis of combinatorial cis-regulation in synthetic and genomic promoters. Nature 457:215–218

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Giniger E, Ptashne M (1988) Cooperative DNA binding of the yeast transcriptional activator GAL4. Proc Natl Acad Sci USA 85:382–386

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gotea V et al (2010) Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers. Genome Res 20:565–577

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • He X, Hohn T, Futterer J (2000) Transcriptional activation of the rice tungro bacilliform virus gene is critically dependent on an activator element located immediately upstream of the TATA box. J Biol Chem 275:11799–11808

    Article  CAS  PubMed  Google Scholar 

  • Herold M, Bartkuhn M, Renkawitz R (2012) CTCF: insights into insulator function during development. Development 139:1045–1057

    Article  CAS  PubMed  Google Scholar 

  • Hertel KJ, Lynch KW, Maniatis T (1997) Common themes in the function of transcription and splicing enhancers. Curr Opin Cell Biol 9:350–357

    Article  CAS  PubMed  Google Scholar 

  • Iyer V, Struhl K (1995) Poly(dA:dT), a ubiquitous promoter element that stimulates transcription via its intrinsic DNA structure. EMBO J 14:2570–2579

    CAS  PubMed Central  PubMed  Google Scholar 

  • Johnson DS, Mortazavi A, Myers RM, Wold B (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316:1497–1502

    Article  CAS  PubMed  Google Scholar 

  • Jolma A et al (2013) DNA-binding specificities of human transcription factors. Cell 152:327–339

    Article  CAS  PubMed  Google Scholar 

  • Juven-Gershon T, Cheng S, Kadonaga JT (2006) Rational design of a super core promoter that enhances gene expression. Nat Methods 3:917–922

    Article  CAS  PubMed  Google Scholar 

  • Kelly TK et al (2012) Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules. Genome Res 22:2497–2506

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kheradpour P et al (2013) Systematic dissection of regulatory motifs in 2000 predicted human enhancers using a massively parallel reporter assay. Genome Res 23:800–811

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Khoury AM, Lee HJ, Lillis M, Lu P (1990) Lac repressor-operator interaction: DNA length dependence. Biochim Biophys Acta 1087:55–60

    Article  CAS  PubMed  Google Scholar 

  • Kim JG, Takeda Y, Matthews BW, Anderson WF (1987) Kinetic studies on Cro repressor-operator DNA interaction. J Mol Biol 196:149–158

    Article  CAS  PubMed  Google Scholar 

  • Kinkhabwala A, Guet CC (2008) Uncovering cis regulatory codes using synthetic promoter shuffling. PLoS One 3:e2030

    Article  PubMed Central  PubMed  Google Scholar 

  • Kinney JB, Murugan A, Callan CG Jr, Cox EC (2010) Using deep sequencing to characterize the biophysical mechanism of a transcriptional regulatory sequence. Proc Natl Acad Sci USA 107:9158–9163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kwasnieski JC, Mogno I, Myers CA, Corbo JC, Cohen BA (2012) Complex effects of nucleotide variants in a mammalian cis-regulatory element. Proc Natl Acad Sci USA 109:19498–19503

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Levine M, Tjian R (2003) Transcription regulation and animal diversity. Nature 424:147–151

    Article  CAS  PubMed  Google Scholar 

  • Lidor Nili E et al (2010) p53 binds preferentially to genomic regions with high DNA-encoded nucleosome occupancy. Genome Res 20:1361–1368

    Article  PubMed Central  PubMed  Google Scholar 

  • Ligr M, Siddharthan R, Cross FR, Siggia ED (2006) Gene expression from random libraries of yeast promoters. Genetics 172:2113–2122

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Melnikov A et al (2012) Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay. Nat Biotechnol 30:271–277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Morin R et al (2008) Profiling the HeLa S3 transcriptome using randomly primed cDNA and massively parallel short-read sequencing. Biotechniques 45:81–94

    Article  CAS  PubMed  Google Scholar 

  • Nguyen DH, D’Haeseleer P (2006) Deciphering principles of transcription regulation in eukaryotic genomes. Mol Syst Biol 2:2006 0012

    Article  PubMed Central  PubMed  Google Scholar 

  • Papatsenko DA et al (2002) Extraction of functional binding sites from unique regulatory regions: the Drosophila early developmental enhancers. Genome Res 12:470–481

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patwardhan RP et al (2009) High-resolution analysis of DNA regulatory elements by synthetic saturation mutagenesis. Nat Biotechnol 27:1173–1175

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patwardhan RP et al (2012) Massively parallel functional dissection of mammalian enhancers in vivo. Nat Biotechnol 30:265–270

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pirrotta V, Gross DS (2005) Epigenetic silencing mechanisms in budding yeast and fruit fly: different paths, same destinations. Mol Cell 18:395–398

    Article  CAS  PubMed  Google Scholar 

  • Ravasi T et al (2010) An atlas of combinatorial transcriptional regulation in mouse and man. Cell 140:744–752

    Article  CAS  PubMed  Google Scholar 

  • Raveh-Sadka T et al (2012) Manipulating nucleosome disfavoring sequences allows fine-tune regulation of gene expression in yeast. Nat Genet 44:743–750

    Article  CAS  PubMed  Google Scholar 

  • Reece-Hoyes JS et al (2005) A compendium of Caenorhabditis elegans regulatory transcription factors: a resource for mapping transcription regulatory networks. Genome Biol 6:R110

    Article  PubMed Central  PubMed  Google Scholar 

  • Reed BD, Charos AE, Szekely AM, Weissman SM, Snyder M (2008) Genome-wide occupancy of SREBP1 and its partners NFY and SP1 reveals novel functional roles and combinatorial regulation of distinct classes of genes. PLoS Genet 4:e1000133

    Article  PubMed Central  PubMed  Google Scholar 

  • Reik W (2007) Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447:425–432

    Article  CAS  PubMed  Google Scholar 

  • Richmond TJ, Davey CA (2003) The structure of DNA in the nucleosome core. Nature 423:145–150

    Article  CAS  PubMed  Google Scholar 

  • Satchwell SC, Drew HR, Travers AA (1986) Sequence periodicities in chicken nucleosome core DNA. J Mol Biol 191:659–675

    Article  CAS  PubMed  Google Scholar 

  • Schlabach MR, Hu JK, Li M, Elledge SJ (2010) Synthetic design of strong promoters. Proc Natl Acad Sci USA 107:2538–2543

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schwartz YB et al (2012) Nature and function of insulator protein binding sites in the Drosophila genome. Genome Res 22:2188–2198

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Segal E, Widom J (2009) Poly(dA:dT) tracts: major determinants of nucleosome organization. Curr Opin Struct Biol 19:65–71

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Segal E, Barash Y, Simon I, Friedman N, Koller D (2002) From promoter sequence to expression: a probabilistic framework. In: Proceeding 6th international conference on research in computational molecular biology (RECOMB), Washington, DC

  • Sharon E et al (2012) Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters. Nat Biotechnol 30:521–530

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Somma MP, Pisano C, Lavia P (1991) The housekeeping promoter from the mouse CpG island HTF9 contains multiple protein-binding elements that are functionally redundant. Nucleic Acids Res 19:2817–2824

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Struhl K (1985) Naturally occurring poly(dA-dT) sequences are upstream promoter elements for constitutive transcription in yeast. Proc Natl Acad Sci USA 82:8419–8423

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Takahashi K et al (1986) Requirement of stereospecific alignments for initiation from the simian virus 40 early promoter. Nature 319:121–126

    Article  CAS  PubMed  Google Scholar 

  • Thastrom A, Bingham LM, Widom J (2004) Nucleosomal locations of dominant DNA sequence motifs for histone-DNA interactions and nucleosome positioning. J Mol Biol 338:695–709

    Article  CAS  PubMed  Google Scholar 

  • Valouev A et al (2011) Determinants of nucleosome organization in primary human cells. Nature 474:516–520

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Walhout AJ (2006) Unraveling transcription regulatory networks by protein-DNA and protein–protein interaction mapping. Genome Res 16:1445–1454

    Article  CAS  PubMed  Google Scholar 

  • Whitfield TW et al (2012) Functional analysis of transcription factor binding sites in human promoters. Genome Biol 13:R50

    Article  PubMed Central  PubMed  Google Scholar 

  • Wunderlich Z, Mirny LA (2009) Different gene regulation strategies revealed by analysis of binding motifs. Trends Genet 25:434–440

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xie X et al (2005) Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434:338–345

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yu M et al (1997) GA-binding protein-dependent transcription initiator elements. Effect of helical spacing between polyomavirus enhancer a factor 3(PEA3)/Ets-binding sites on initiator activity. J Biol Chem 272:29060–29067

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by grants to E.S. from the National Institute of Health (NIH) and the European Research Council (ERC). S.WG. is a Clore scholar.

Author information

Authors and Affiliations

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

    Shira Weingarten-Gabbay & Eran Segal

Authors
  1. Shira Weingarten-Gabbay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eran Segal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eran Segal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weingarten-Gabbay, S., Segal, E. The grammar of transcriptional regulation. Hum Genet 133, 701–711 (2014). https://doi.org/10.1007/s00439-013-1413-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-013-1413-1

Keywords

Search

Navigation