Abstract
Enhancers and insulators are regulatory DNA sequences that can work over a large distance. Efficient action over a distance clearly requires special mechanisms for facilitating communication between a regulatory region and its target. Studies from our laboratory identified DNA supercoiling as primary factor that mediates efficient enhancer-promoter communication over a distance in prokaryotes through a “DNA slithering” mechanism. These studies allowed rational design and construction of an insulator that can block enhancer action over a distance both in vitro and in vivo. Our most recent studies suggest that eukaryotic chromatin structure can support action over a distance using similar principles, but in a mechanistically distinct way.
Similar content being viewed by others
References
Bondarenko V.A., Liu Y.V., Jiang Y.I., Studitsky V.M. 2003. Communication over a large distance: enhancers and insulators. Biochem. Cell. Biol. 81, 241–251.
de Laat W., Klous P., Kooren J., Noordermeer D., Palstra R.J., Simonis M., Splinter E., Grosveld F. 2008. Three-dimensional organization of gene expression in erythroid cells. Curr. Top. Dev. Biol. 82, 117–139.
Wallace J.A., Felsenfeld G. 2007. We gather together: Insulators and genome organization. Curr. Opin. Genet. Dev. 17, 400–407.
Maksimenko O., Golovnin A., Georgiev P. 2008. Enhancer-promoter communication is regulated by insulator pairing in a Drosophila model bigenic locus. Mol. Cell. Biol. 28, 5469–5477.
Bellomy G.R., Record M.T., Jr. 1990. Stable DNA loops in vivo and in vitro: roles in gene regulation at a distance and in biophysical characterization of DNA. Progr. Nucleic Acid Res. Mol. Biol. 39, 81–128.
Liu Y., Bondarenko V., Ninfa A., Studitsky V.M. 2001. DNA supercoiling allows enhancer action over a large distance. Proc. Natl. Acad. Sci. USA. 98, 14883–14888.
Guarente L. 1988. UASs and enhancers: common mechanism of transcriptional activation in yeast and mammals. Cell. 52, 303–305.
Studitsky V.M. 1991. Allosteric mechanism of enhancer action? FEBS Lett. 280, 5–7.
Studitsky V.M., Khrapko K.R. 1990. Enhancers, DNA loops and stable complexes: A mechanism of transcription activation. Mol. Biol. 24, 909–919.
Gralla J.D. 1996. Activation and repression of E. coli promoters. Curr. Opin. Genet. Dev. 6, 526–530.
Buck M., Gallegos M.T., Studholme D.J., Guo Y., Gralla J.D. 2000. The bacterial enhancer-dependent sigma(54) (sigma(N)) transcription factor. J. Bacteriol. 182, 4129–4136.
Magasanik B. 1989. Regulation of transcription of the glnALG operon of Escherichia coli by protein phosphorylation. Biochimie. 71, 1005–1012.
Hwang I., Thorgeirsson T., Lee J., Kustu S., Shin Y.K. 1999. Physical evidence for a phosphorylation-dependent conformational change in the enhancer-binding protein NtrC. Proc. Natl. Acad. Sci. USA. 96, 4880–4885.
Wyman C., Rombel I., North A.K., Bustamante C., Kustu S. 1997. Unusual oligomerization required for activity of NtrC, a bacterial enhancer-binding protein. Science. 275, 1658–1661.
Porter S.C., North A.K., Wedel A.B., Kustu S. 1993. Oligomerization of NTRC at the glnA enhancer is required for transcriptional activation. Genes Dev. 7, 2258–2273.
Wedel A., Kustu S. 1995. The bacterial enhancer-binding protein NTRC is a molecular machine: ATP hydrolysis is coupled to transcriptional activation. Genes Dev. 9, 2042–2052.
Su W., Porter S., Kustu S., Echols H. 1990. DNA-looping and enhancer activity: Association between DNA-bound NtrC activator and RNA polymerase at the bacterial glnA promoter. Proc. Natl. Acad. Sci. USA. 87, 5504–5508.
Rippe K., Guthold M., von Hippel P.H., Bustamante C. 1997. Transcriptional activation via DNA-looping: Visualization of intermediates in the activation pathway of E. coli RNA polymerase x sigma 54 holoenzyme by scanning force microscopy. J. Mol. Biol. 270, 125–138.
Sasse-Dwight S., Gralla J.D. 1988. Probing the Escherichia coli glnALG upstream activation mechanism in vivo. Proc. Natl. Acad. Sci. USA. 85, 8934–8938.
Popham D.L., Szeto D., Keener J., Kustu S. 1989. Function of a bacterial activator protein that binds to transcriptional enhancers. Science. 243, 629–635.
Bondarenko V., Liu Y., Ninfa A., Studitsky V.M. 2002. Action of prokaryotic enhancer over a distance does not require continued presence of promoter-bound sigma54 subunit. Nucleic Acids Res. 30, 636–642.
Rubtsov M.A., Polikanov Y.S., Bondarenko V.A., Wang Y.H., Studitsky V.M. 2006. Chromatin structure can strongly facilitate enhancer action over a distance. Proc. Natl. Acad. Sci. USA. 103, 17690–17695.
Tolhuis B., Palstra R.J., Splinter E., Grosveld F., de Laat W. 2002. Looping and interaction between hypersensitive sites in the active beta-globin locus. Mol. Cell. 10, 1453–1465.
Carter D., Chakalova L., Osborne C.S., Dai Y.F., Fraser P. 2002. Long-range chromatin regulatory interactions in vivo. Nature Genet. 32, 623–626.
Ferrai C., Munari D., Luraghi P., Pecciarini L., Cangi M.G., Doglioni C., Blasi F., Crippa M.P. 2007. A transcription-dependent micrococcal nuclease-resistant fragment of the urokinase-type plasminogen activator promoter interacts with the enhancer. J. Biol. Chem. 282, 12537–12546.
Vernimmen D., De Gobbi M., Sloane-Stanley J.A., Wood W.G., Higgs D.R. 2007. Long-range chromosomal interactions regulate the timing of the transition between poised and active gene expression. EMBO J. 26, 2041–2051.
Jhunjhunwala S., van Zelm M.C., Peak M.M., Cutchin S., Riblet R., van Dongen J.J., Grosveld F. G., Knoch T.A., Murre C. 2008. The 3D structure of the immunoglobulin heavy-chain locus: implications for long-range genomic interactions. Cell. 133, 265–279.
Ho Y., Elefant F., Liebhaber S.A., Cooke N.E. 2006. Locus control region transcription plays an active role in long-range gene activation. Mol. Cell. 23, 365–375.
Zhu X., Ling J., Zhang L., Pi W., Wu M., Tuan D. 2007. A facilitated tracking and transcription mechanism of long-range enhancer function. Nucleic Acids Res. 35, 5532–5544.
Ling J., Ainol L., Zhang L., Yu X., Pi W., Tuan D. 2004. HS2 enhancer function is blocked by a transcriptional terminator inserted between the enhancer and the promoter. J. Biol. Chem. 279, 51704–51713.
Zhao H., Kim A., Song S.H., Dean A. 2006. Enhancer blocking by chicken beta-globin 5′-HS4: Role of enhancer strength and insulator nucleosome depletion. J. Biol. Chem. 281, 30573–30580.
Hatzis P., Talianidis I. 2002. Dynamics of enhancer-promoter communication during differentiation-Induced gene activation. Mol. Cell. 10, 1467–1477.
Byrd K., Corces V.G. 2003. Visualization of chromatin domains created by the gypsy insulator of Drosophila. J. Cell. Biol. 162, 565–574.
Yusufzai T.M., Tagami H., Nakatani Y., Felsenfeld G. 2004. CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Mol. Cell. 13, 291–298.
Ameres S.L., Drueppel L., Pfleiderer K., Schmidt A., Hillen W., Berens C. 2005. Inducible DNA-loop formation blocks transcriptional activation by an SV40 enhancer. EMBO J. 24, 358–367.
Splinter E., Heath H., Kooren J., Palstra R.J., Klous P., Grosveld F., Galjart N., de Laat W. 2006. CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. Genes Dev. 20, 2349–2354.
Cai H.N., Shen P. 2001. Effects of cis arrangement of chromatin insulators on enhancer-blocking activity. Science. 291, 493–495.
Muravyova E., Golovnin A., Gracheva E., Parshikov A., Belenkaya T., Pirrotta V., Georgiev P. 2001. Loss of insulator activity by paired Su(Hw) chromatin insulators. Science. 291, 495–498.
Maksimenko O., Golovnin A., Georgiev P. 2008. Enhancer-promoter communication is regulated by insulator pairing in a Drosophila model bigenic locus. Mol. Cell. Biol. (28, 5469–5477.
Claverie-Martin F., Magasanik B. 1992. Positive and negative effects of DNA bending on activation of transcription from a distant site. J. Mol. Biol. 227, 996–1008.
Vologodskii A., Cozzarelli N.R. 1996. Effect of super-coiling on the juxtaposition and relative orientation of DNA sites. Biophys. J. 70, 2548–2556.
Huang J., Schlick T., Vologodskii A. 2001. Dynamics of site juxtaposition in supercoiled DNA. Proc. Natl. Acad. Sci. USA. 98, 968–973.
Bondarenko V.A., Jiang Y.I., Studitsky V.M. 2003. Rationally designed insulator-like elements can block enhancer action in vitro. EMBO J. 22, 4728–4737.
Barkley M.D., Riggs A.D., Jobe A., Burgeois S. 1975. Interaction of effecting ligands with lac repressor and repressor-operator complex. Biochemistry. 14, 1700–1712.
O’Gorman R.B., Rosenberg J.M., Kallai O.B., Dickerson R.E., Itakura K., Riggs A.D., Matthews K.S. 1980. Equilibrium binding of inducer to lac repressor/operator DNA complex. J. Biol. Chem. 255, 10107–10114.
Whitson P.A., Olson J.S., Matthews K.S. 1986. Thermodynamic analysis of the lactose repressor-operator DNA interaction. Biochemistry. 25, 3852–3858.
Whitson P.A., Hsieh W.T., Wells R.D., Matthews K.S. 1987. Influence of supercoiling and sequence context on operator DNA binding with lac repressor. J. Biol. Chem. 262, 14592–14599.
Hsieh W.T., Whitson P.A., Matthews K.S., Wells R.D. 1987. Influence of sequence and distance between two operators on interaction with the lac repressor. J. Biol. Chem. 262, 14583–14591.
Kramer H., Niemoller M., Amouyal M., Revet B., von Wilcken-Bergmann B., Muller-Hill B. 1987. lac repressor forms loops with linear DNA carrying two suitably spaced lac operators. EMBO J. 6, 1481–1491.
Kramer H., Amouyal M., Nordheim A., Muller-Hill B. 1988. DNA supercoiling changes the spacing requirement of two lac operators for DNA loop formation with lac repressor. EMBO J. 7, 547–556.
Chen J., Alberti S., Matthews K.S. 1994. Wild-type operator binding and altered cooperativity for inducer binding of lac repressor dimer mutant R3. lac. J. Biol. Chem. 269, 12482–12487.
Polikanov Y.S., Bondarenko V.A., Tchernaenko V., Jiang Y.I., Lutter L.C., Vologodskii A., Studitsky V.M. 2007. Probability of the site juxtaposition determines the rate of protein-mediated DNA looping. Biophys. J. 93, 2726–2731.
Cai H., Levine M. 1995. Modulation of enhancer-promoter interactions by insulators in the Drosophila embryo. Nature. 376, 533–536.
Scott K.S., Geyer P.K. 1995. Effects of the su(Hw) insulator protein on the expression of the divergently transcribed Drosophila yolk protein genes. EMBO J. 14, 6258–6267.
Dorsett D. 1993. Distance-independent inactivation of an enhancer by the suppressor of Hairy-wing DNA-binding protein of Drosophila. Genetics. 134, 1135–1144.
Golovnin A., Gause M., Georgieva S., Gracheva E., Georgiev P. 1999. The su(Hw) insulator can disrupt enhancer-promoter interactions when located more than 20 kilobases away from the Drosophila achaete-scute complex. Mol. Cell. Biol. 19, 3443–3456.
West A.G., Gaszner M., Felsenfeld G. 2002. Insulators: Many functions, many mechanisms. Genes Dev. 16, 271–288.
Fraser P., Bickmore W. 2007. Nuclear organization of the genome and the potential for gene regulation. Nature. 447, 413–417.
Morey C., Da Silva N.R., Kmita M., Duboule D., Bickmore W.A. 2008. Ectopic nuclear reorganisation driven by a Hoxb1 transgene transposed into Hoxd. J. Cell. Sci. 121, 571–577.
Horowitz-Scherer R.A., Woodcock C.L. 2006. Organization of interphase chromatin. Chromosoma. 115, 1–14.
Gilbert N., Boyle S., Fiegler H., Woodfine K., Carter N.P., Bickmore W.A. 2004. Chromatin architecture of the human genome: Gene-rich domains are enriched in open chromatin fibers. Cell. 118, 555–566.
Grigoryev S.A. 2004. Keeping fingers crossed: Heterochromatin spreading through interdigitation of nucleosome arrays. FEBS Lett. 564, 4–8.
Tremethick D.J. 2007. Higher-order structures of chromatin: The elusive 30 nm fiber. Cell. 128, 651–654.
Schwarz P.M., Hansen J.C. 1994. Formation and stability of higher order chromatin structures: Contributions of the histone octamer. J. Biol. Chem. 269, 16284–16289.
Schalch T., Duda S., Sargent D.F., Richmond T.J. 2005. X-ray structure of a tetranucleosome and its implications for the chromatin fibre. Nature. 436, 138–141.
Dorigo B., Schalch T., Kulangara A., Duda S., Schroeder R.R., Richmond T.J. 2004. Nucleosome arrays reveal the two-start organization of the chromatin fiber. Science. 306, 1571–1573.
Robinson P.J., Fairall L., Huynh V.A., Rhodes D. 2006. EM measurements define the dimensions of the “30-nm” chromatin fiber: evidence for a compact, interdigitated structure. Proc. Natl. Acad. Sci. USA. 103, 6506–6511.
Bondarenko V., Liu Y.V., Ninfa A.J., Studitsky V.M. 2003. Assay of prokaryotic enhancer activity over a distance in vitro. Methods Enzymol. 370, 324–337.
Stein A., Dalal Y., Fleury T.J. 2002. Circle ligation of in vitro assembled chromatin indicates a highly flexible structure. Nucleic Acids Res. 30, 5103–5109.
Ringrose L., Chabanis S., Angrand P.O., Woodroofe C., Stewart A.F. 1999. Quantitative comparison of DNA looping in vitro and in vivo: Chromatin increases effective DNA flexibility at short distances. EMBO J. 18, 6630–6641, 6630–6641.
Gordon F., Luger K., Hansen J.C. 2005. The core histone N-terminal tail domains function independently and additively during salt-dependent oligomerization of nucleosomal arrays. J. Biol. Chem. 280, 33701–33706.
Polikanov Y.S., Rubtsov M.A., Studitsky V.M. 2007. Biochemical analysis of enhancer-promoter communication in chromatin. Methods. 41, 250–258.
Li G., Levitus M., Bustamante C., Widom J. 2005. Rapid spontaneous accessibility of nucleosomal DNA. Nature Struct. Mol. Biol. 12, 46–53.
Anderson J.D., Thastrom A., Widom J. 2002. Spontaneous access of proteins to buried nucleosomal DNA target sites occurs via a mechanism that is distinct from nucleosome translocation. Mol. Cell. Biol. 22, 7147–7157.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published in Russian in Molekulyarnaya Biologiya, 2009, Vol. 43, No. 2, pp. 204–214.
The article was translated by the author.
Rights and permissions
About this article
Cite this article
Studitsky, V.M. Mechanisms of distant enhancer action on DNA and in chromatin. Mol Biol 43, 188–197 (2009). https://doi.org/10.1134/S0026893309020022
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0026893309020022