Abstract
One of the fascinating questions in biology is to understand how an identical genome can give rise to distinct tissues with different functions, for example, brain and muscle. A key role in selectively decoding the genome is played by transcription factors (TFs), which bind to specific DNA sequences to help specify if and how much of a gene is expressed in a particular tissue. In a simple scenario, binding of TFs near a gene would result in activation of gene expression whereas in the absence of binding the gene would not be expressed. One of the objectives of computational biology is to use the genomic sequence to predict where TFs bind and to both qualitatively and quantitatively predict which genes it regulates. In this chapter, we will discuss how the information encoded in the genome in the form of DNA can serve as a discreet code where combinations of As, Ts, Cs, and Gs specify which TFs can bind. Further, structural features of DNA can be read by proteins to influence their structure and fine-tune their activity towards target genes. In practice, predicting genome-wide binding patterns of TFs based on sequence is problematic and even when we know where TFs bind, all bets appear to be off regarding the effect of TF binding on the regulation of genes. At the moment it sometimes seems as if 1 + 1 ≠ 2 when studying gene regulation. However, this mostly reflects our lack of understanding of the signaling inputs that specify if a gene is activated and at which level it is expressed. For example, in this chapter we will discuss how taking the three-dimensional organization of the genome and the chromatin context in which these binding sites are embedded into account can improve the link between binding of TFs and the regulation of genes. Eventually, by adding more and more pieces of the puzzle, we hope to identify what is missing in our current equations to model gene expression.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Chiang, C., et al.: Manifestation of the limb prepattern: limb development in the absence of sonic hedgehog function. Dev. Biol. 236(2), 421–435 (2001)
Struhl, G.: A homoeotic mutation transforming leg to antenna in Drosophila. Nature 292(5824), 635–638 (1981)
Donehower, L.A., et al.: Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356(6366), 215–221 (1992)
Consortium, E.P.: An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414), 57–74 (2012)
Bulger, M., Groudine, M.: Functional and mechanistic diversity of distal transcription enhancers. Cell 144(3), 327–339 (2011)
de Laat, W., Duboule, D.: Topology of mammalian developmental enhancers and their regulatory landscapes. Nature 502(7472), 499–506 (2013)
Calo, E., Wysocka, J.: Modification of enhancer chromatin: what, how, and why? Mol. Cell 49(5), 825–837 (2013)
Meijsing, S.H.: Mechanisms of glucocorticoid-regulated gene transcription. Adv. Exp. Med. Biol. 872, 59–81 (2015)
Zhang, Z., et al.: Evolutionary optimization of transcription factor binding motif detection. Adv. Exp. Med. Biol. 827, 261–274 (2015)
Zhang, C., et al.: A clustering property of highly-degenerate transcription factor binding sites in the mammalian genome. Nucleic Acids Res. 34(8), 2238–2246 (2006)
Wu, J., Bresnick, E.H.: Glucocorticoid and growth factor synergism requirement for Notch4 chromatin domain activation. Mol. Cell Biol. 27(6), 2411–2422 (2007)
Rao, N.A., et al.: Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes. Genome Res. 21(9), 1404–1416 (2011)
Biddie, S.C., et al.: Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43(1), 145–155 (2011)
West, J.A., et al.: Nucleosomal occupancy changes locally over key regulatory regions during cell differentiation and reprogramming. Nat. Commun. 5, 4719 (2014)
He, H.H., et al.: Differential DNase I hypersensitivity reveals factor-dependent chromatin dynamics. Genome Res. 22(6), 1015–1025 (2012)
Gertz, J., et al.: Distinct properties of cell-type-specific and shared transcription factor binding sites. Mol. Cell 52(1), 25–36 (2013)
Morikawa, M., et al.: ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif. Nucleic Acids Res. 39(20), 8712–8727 (2011)
Kvon, E.Z., et al.: Genome-scale functional characterization of Drosophila developmental enhancers in vivo. Nature 512(7512), 91–95 (2014)
Weirauch, M.T., et al.: Evaluation of methods for modeling transcription factor sequence specificity. Nat. Biotechnol. 31(2), 126–134 (2013)
Cusanovich, D.A., et al.: The functional consequences of variation in transcription factor binding. PLoS Genet. 10(3), e1004226 (2014)
Gitter, A., et al.: Backup in gene regulatory networks explains differences between binding and knockout results. Mol. Syst. Biol. 5, 276 (2009)
Creyghton, M.P., et al.: Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl. Acad. Sci. U. S. A. 107(50), 21931–21936 (2010)
Heintzman, N.D., et al.: Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39(3), 311–318 (2007)
Hardison, R.C., Taylor, J.: Genomic approaches towards finding cis-regulatory modules in animals. Nat. Rev. Genet. 13(7), 469–483 (2012)
Kwasnieski, J.C., et al.: High-throughput functional testing of ENCODE segmentation predictions. Genome Res. 24(10), 1595–1602 (2014)
Frankel, N., et al.: Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466(7305), 490–493 (2010)
Spivakov, M.: Spurious transcription factor binding: non-functional or genetically redundant? Bioessays 36(8), 798–806 (2014)
So, A.Y., et al.: Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor. PLoS Genet. 3(6), e94 (2007)
Amano, T., et al.: Chromosomal dynamics at the Shh locus: limb bud-specific differential regulation of competence and active transcription. Dev. Cell 16(1), 47–57 (2009)
Levings, P.P., Bungert, J.: The human beta-globin locus control region. Eur. J. Biochem. 269(6), 1589–1599 (2002)
Hilton, I.B., et al.: Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat. Biotechnol. 33(5), 510–517 (2015)
Tolhuis, B., et al.: Looping and interaction between hypersensitive sites in the active beta-globin locus. Mol. Cell 10(6), 1453–1465 (2002)
Dekker, J., et al.: Capturing chromosome conformation. Science 295(5558), 1306–1311 (2002)
Dekker, J., Marti-Renom, M.A., Mirny, L.A.: Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat. Rev. Genet. 14(6), 390–403 (2013)
Dixon, J.R., et al.: Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485(7398), 376–380 (2012)
Zuin, J., et al.: Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc. Natl. Acad. Sci. 111(3), 996–1001 (2014)
Nagano, T., et al.: Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 502(7469), 59–64 (2013)
Rao, S.S., et al.: A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159(7), 1665–1680 (2014)
Fang, F., et al.: Coactivators p300 and CBP maintain the identity of mouse embryonic stem cells by mediating long-range chromatin structure. Stem Cells 32(7), 1805–1816 (2014)
Drissen, R., et al.: The active spatial organization of the beta-globin locus requires the transcription factor EKLF. Genes Dev. 18(20), 2485–2490 (2004)
Bouwman, B.A., de Laat, W.: Getting the genome in shape: the formation of loops, domains and compartments. Genome Biol. 16, 154 (2015)
Vakoc, C.R., et al.: Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1. Mol. Cell 17(3), 453–462 (2005)
Jin, F., et al.: A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503(7475), 290–294 (2013)
Kilpinen, H., et al.: Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science 342(6159), 744–747 (2013)
Corradin, O., et al.: Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res. 24(1), 1–13 (2014)
Wang, J., et al.: In vitro DNA-binding profile of transcription factors: methods and new insights. J. Endocrinol. 210(1), 15–27 (2011)
Slattery, M., et al.: Cofactor binding evokes latent differences in DNA binding specificity between Hox proteins. Cell 147(6), 1270–1282 (2011)
Stella, S., Cascio, D., Johnson, R.C.: The shape of the DNA minor groove directs binding by the DNA-bending protein Fis. Genes Dev. 24(8), 814–826 (2010)
Ramos, A.I., Barolo, S.: Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368(1632), 20130018 (2013)
Crocker, J., et al.: Low affinity binding site clusters confer hox specificity and regulatory robustness. Cell 160(1-2), 191–203 (2015)
He, X., Duque, T.S., Sinha, S.: Evolutionary origins of transcription factor binding site clusters. Mol. Biol. Evol. 29(3), 1059–1070 (2012)
Gao, R., Stock, A.M.: Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics. mBio 6(3), e00686-15 (2015)
Bain, D.L., et al.: Glucocorticoid receptor-DNA interactions: binding energetics are the primary determinant of sequence-specific transcriptional activity. J. Mol. Biol. 422(1), 18–32 (2012)
Segal, E., et al.: Predicting expression patterns from regulatory sequence in Drosophila segmentation. Nature 451(7178), 535–540 (2008)
Garcia, H.G., et al.: Operator sequence alters gene expression independently of transcription factor occupancy in bacteria. Cell Rep. 2(1), 150–161 (2012)
Meijsing, S.H., et al.: DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324(5925), 407–410 (2009)
Hammar, P., et al.: Direct measurement of transcription factor dissociation excludes a simple operator occupancy model for gene regulation. Nat. Genet. 46(4), 405–408 (2014)
Zhang, J., et al.: DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex. Nat. Struct. Mol. Biol. 18(5), 556–563 (2011)
Rohs, R., et al.: Nuance in the double-helix and its role in protein-DNA recognition. Curr. Opin. Struct. Biol. 19(2), 171–177 (2009)
Meyer, M.B., Benkusky, N.A., Pike, J.W.: Selective distal enhancer control of the Mmp13 gene identified through clustered regularly interspaced short palindromic repeat (CRISPR) genomic deletions. J. Biol. Chem. 290(17), 11093–11107 (2015)
Diamond, M.I., et al.: Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science 249(4974), 1266–1272 (1990)
John, S., et al.: Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat. Genet. 43(3), 264–268 (2011)
Arnold, C.D., et al.: Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339(6123), 1074–1077 (2013)
Zabidi, M.A., et al.: Enhancer-core-promoter specificity separates developmental and housekeeping gene regulation. Nature 518(7540), 556–559 (2015)
Dupin, C., et al.: Treatment of head and neck paragangliomas with external beam radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 89(2), 353–359 (2014)
Korkmaz, G., et al.: Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9. Nat. Biotechnol. 34(2), 192–198 (2016)
Maeder, M.L., et al.: CRISPR RNA-guided activation of endogenous human genes. Nat Methods 10(10), 977–979 (2013)
Mendenhall, E.M., et al.: Locus-specific editing of histone modifications at endogenous enhancers. Nat. Biotechnol. 31(12), 1133–1136 (2013)
Lupianez, D.G., et al.: Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161(5), 1012–1025 (2015)
Zhang, X., et al.: Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat. Genet. 48(2), 176–182 (2016)
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Thormann, V., Borschiwer, M., Meijsing, S.H. (2016). Transcriptional Regulation: When 1+1≠2. In: Rogato, A., Zazzu, V., Guarracino, M. (eds) Dynamics of Mathematical Models in Biology . Springer, Cham. https://doi.org/10.1007/978-3-319-45723-9_1
Download citation
DOI: https://doi.org/10.1007/978-3-319-45723-9_1
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-45722-2
Online ISBN: 978-3-319-45723-9
eBook Packages: Mathematics and StatisticsMathematics and Statistics (R0)