메뉴 건너뛰기




Volumn 4, Issue OCT, 2013, Pages

The effects of transcription factor competition on gene regulation

Author keywords

Facilitated diffusion; Molecular crowding; Noise; Roadblocks; Transcription factors

Indexed keywords


EID: 84885406352     PISSN: None     EISSN: 16648021     Source Type: Journal    
DOI: 10.3389/fgene.2013.00197     Document Type: Article
Times cited : (25)

References (44)
  • 1
    • 33745287724 scopus 로고    scopus 로고
    • Noise in protein expression scales with natural protein abundance
    • doi:10.1038/ng1807
    • Bar-Even, A., Paulsson, J., Maheshri, N., Carmi, M., O'Shea, E., Pilpel, Y., et al. (2006). Noise in protein expression scales with natural protein abundance. Nat. Genet. 38, 636-643. doi:10.1038/ng1807.
    • (2006) Nat. Genet. , vol.38 , pp. 636-643
    • Bar-Even, A.1    Paulsson, J.2    Maheshri, N.3    Carmi, M.4    O'Shea, E.5    Pilpel, Y.6
  • 2
    • 84872513867 scopus 로고    scopus 로고
    • In vivo facilitated diffusion model
    • doi:10.1371/journal.pone.0053956
    • Bauer, M., and Metzler, R. (2013). In vivo facilitated diffusion model. PLoS ONE 8:e53956. doi:10.1371/journal.pone.0053956.
    • (2013) PLoS ONE , vol.8
    • Bauer, M.1    Metzler, R.2
  • 3
    • 25144450143 scopus 로고    scopus 로고
    • Contributions of low molecule number and chromosomal positioning to stochastic gene expression
    • doi:10.1038/ng1616
    • Becskei, A., Kaufmann, B. B., and van Oudenaarden, A. (2005). Contributions of low molecule number and chromosomal positioning to stochastic gene expression. Nat. Genet. 37, 937-944. doi:10.1038/ng1616.
    • (2005) Nat. Genet. , vol.37 , pp. 937-944
    • Becskei, A.1    Kaufmann, B.B.2    van Oudenaarden, A.3
  • 4
    • 0019887628 scopus 로고
    • Diffusion-driven mechanisms of protein translocation on nucleic acids. 1. Models and theory
    • doi:10.1021/bi00527a028
    • Berg, O. G., Winter, R. B., and von Hippel, P. H. (1981). Diffusion-driven mechanisms of protein translocation on nucleic acids. 1. Models and theory. Biochemistry 20, 6929-6948. doi:10.1021/bi00527a028.
    • (1981) Biochemistry , vol.20 , pp. 6929-6948
    • Berg, O.G.1    Winter, R.B.2    von Hippel, P.H.3
  • 5
    • 47249153641 scopus 로고    scopus 로고
    • Sliding and jumping of single EcoRV restriction enzymes on non-cognate DNA
    • doi:10.1093/nar/gkn376
    • Bonnet, I., Biebricher, A., Porte, P.-L., Loverdo, C., Benichou, O., Voituriez, R., et al. (2008). Sliding and jumping of single EcoRV restriction enzymes on non-cognate DNA. Nucleic Acids Res. 36, 4118-4127. doi:10.1093/nar/gkn376.
    • (2008) Nucleic Acids Res. , vol.36 , pp. 4118-4127
    • Bonnet, I.1    Biebricher, A.2    Porte, P.-L.3    Loverdo, C.4    Benichou, O.5    Voituriez, R.6
  • 6
    • 84867517832 scopus 로고    scopus 로고
    • Facilitated diffusion on mobile DNA:configurational traps and sequence heterogeneity
    • doi:10.1103/PhysRevLett.109.168103
    • Brackley, C. A., Cates, M. E., and Marenduzzo, D. (2012). Facilitated diffusion on mobile DNA:configurational traps and sequence heterogeneity. Phys. Rev. Lett. 109:168103. doi:10.1103/PhysRevLett.109.168103.
    • (2012) Phys. Rev. Lett. , vol.109 , pp. 168103
    • Brackley, C.A.1    Cates, M.E.2    Marenduzzo, D.3
  • 7
    • 84884268708 scopus 로고    scopus 로고
    • Intracellular facilitated diffusion:searchers, crowders, and blockers
    • doi:10.1103/PhysRevLett.111.108101
    • Brackley, C. A., Cates, M. E., and Marenduzzo, D. (2013). Intracellular facilitated diffusion:searchers, crowders, and blockers. Phys. Rev. Lett. 111:108101. doi:10.1103/PhysRevLett.111.108101.
    • (2013) Phys. Rev. Lett. , vol.111 , pp. 108101
    • Brackley, C.A.1    Cates, M.E.2    Marenduzzo, D.3
  • 8
    • 61449155349 scopus 로고    scopus 로고
    • Models of transcription factor binding:sensitivity of activation functions to model assumptions
    • doi:10.1016/j.jtbi.2008.11.026
    • Chu, D., Zabet, N. R., and Mitavskiy, B. (2009). Models of transcription factor binding:sensitivity of activation functions to model assumptions. J. Theor. Biol. 257, 419-429. doi:10.1016/j.jtbi.2008.11.026.
    • (2009) J. Theor. Biol. , vol.257 , pp. 419-429
    • Chu, D.1    Zabet, N.R.2    Mitavskiy, B.3
  • 9
    • 34249932435 scopus 로고    scopus 로고
    • Probing transcription factor dynamics at the single-molecule level in a living cell
    • doi:10.1126/science.1141967
    • Elf, J., Li, G.-W., and Xie, X. S. (2007). Probing transcription factor dynamics at the single-molecule level in a living cell. Science 316, 1191-1194. doi:10.1126/science.1141967.
    • (2007) Science , vol.316 , pp. 1191-1194
    • Elf, J.1    Li, G.-W.2    Xie, X.S.3
  • 10
    • 33646945653 scopus 로고    scopus 로고
    • Strong physical constraints on sequence-specific target location by proteins on DNA molecules
    • doi:10.1093/nar/gkl271
    • Flyvbjerg, H., Keatch, S. A., and Dryden, D. T. (2006). Strong physical constraints on sequence-specific target location by proteins on DNA molecules. Nucleic Acids Res. 34, 2550-2557. doi:10.1093/nar/gkl271.
    • (2006) Nucleic Acids Res. , vol.34 , pp. 2550-2557
    • Flyvbjerg, H.1    Keatch, S.A.2    Dryden, D.T.3
  • 11
    • 84857712855 scopus 로고    scopus 로고
    • Facilitated diffusion on confined DNA
    • doi:10.1103/PhysRevE.85.021919
    • Foffano, G., Marenduzzo, D., and Orlandini, E. (2012). Facilitated diffusion on confined DNA. Phys. Rev. E 85:021919. doi:10.1103/PhysRevE.85.021919.
    • (2012) Phys. Rev. E , vol.85 , pp. 021919
    • Foffano, G.1    Marenduzzo, D.2    Orlandini, E.3
  • 12
    • 80051728360 scopus 로고    scopus 로고
    • How do hox transcription factors find their target genes in the nucleus of living cells?
    • doi:10.1051/jbio/2011012
    • Gehring, W. J. (2011). How do hox transcription factors find their target genes in the nucleus of living cells? Biol. Aujourdhui 205, 75-85. doi:10.1051/jbio/2011012.
    • (2011) Biol. Aujourdhui , vol.205 , pp. 75-85
    • Gehring, W.J.1
  • 13
    • 0037126028 scopus 로고    scopus 로고
    • Physical constraints and functional characteristics of transcription factor-DNA interactions
    • doi:10.1073/pnas.192693599
    • Gerland, U., Moroz, J. D., and Hwa, T. (2002). Physical constraints and functional characteristics of transcription factor-DNA interactions. PNAS 99, 12015-12020. doi:10.1073/pnas.192693599.
    • (2002) PNAS , vol.99 , pp. 12015-12020
    • Gerland, U.1    Moroz, J.D.2    Hwa, T.3
  • 14
    • 0017030517 scopus 로고
    • A general method for numerically simulating the stochastic time evolution of coupled chemical reactions
    • doi:10.1016/0021-9991(76)90041-3
    • Gillespie, D. T. (1976). A general method for numerically simulating the stochastic time evolution of coupled chemical reactions. J. Comput. Phys. 22, 403-434. doi:10.1016/0021-9991(76)90041-3.
    • (1976) J. Comput. Phys. , vol.22 , pp. 403-434
    • Gillespie, D.T.1
  • 15
    • 33645429016 scopus 로고
    • Exact stochastic simulation of coupled chemical reactions
    • doi:10.1021/j100540a008
    • Gillespie, D. T. (1977). Exact stochastic simulation of coupled chemical reactions. J. Phys. Chem. 81, 2340-2361. doi:10.1021/j100540a008.
    • (1977) J. Phys. Chem. , vol.81 , pp. 2340-2361
    • Gillespie, D.T.1
  • 16
    • 3042579602 scopus 로고    scopus 로고
    • How do site-specific DNA-binding proteins find their targets?
    • doi:10.1093/nar/gkh624
    • Halford, S. E., and Marko, J. F. (2004). How do site-specific DNA-binding proteins find their targets? Nucleic Acids Res. 32, 3040-3052. doi:10.1093/nar/gkh624.
    • (2004) Nucleic Acids Res. , vol.32 , pp. 3040-3052
    • Halford, S.E.1    Marko, J.F.2
  • 17
    • 84862624197 scopus 로고    scopus 로고
    • The lac repressor displays facilitated diffusion in living cells
    • doi:10.1126/science.1221648
    • Hammar, P., Leroy, P., Mahmutovic, A., Marklund, E. G., Berg, O. G., and Elf, J. (2012). The lac repressor displays facilitated diffusion in living cells. Science 336, 1595-1598. doi:10.1126/science.1221648.
    • (2012) Science , vol.336 , pp. 1595-1598
    • Hammar, P.1    Leroy, P.2    Mahmutovic, A.3    Marklund, E.G.4    Berg, O.G.5    Elf, J.6
  • 18
    • 33846002036 scopus 로고    scopus 로고
    • Transcriptional regulation by competing transcription factor modules
    • doi:10.1371/journal.pcbi.0020164
    • Hermsen, R., Tans, S., and ten Wolde, P. R. (2006). Transcriptional regulation by competing transcription factor modules. PLoS Comput. Biol. 2, 1552-1560. doi:10.1371/journal.pcbi.0020164.
    • (2006) PLoS Comput. Biol. , vol.2 , pp. 1552-1560
    • Hermsen, R.1    Tans, S.2    ten Wolde, P.R.3
  • 19
    • 0027749617 scopus 로고
    • Visualization of single molecules of rna polymerase sliding along dna
    • doi:10.1126/science.8248804
    • Kabata, H., Kurosawa, O., I, Arai, M. W., Margarson, S., Glass, R., and Shimamoto, N. (1993). Visualization of single molecules of rna polymerase sliding along dna. Science 262, 1561-1563. doi:10.1126/science.8248804.
    • (1993) Science , vol.262 , pp. 1561-1563
    • Kabata, H.1    Kurosawa, O.I.2    Arai, M.W.3    Margarson, S.4    Glass, R.5    Shimamoto, N.6
  • 20
    • 63849284078 scopus 로고    scopus 로고
    • Effects of macromolecular crowding and dna looping on gene regulation kinetics
    • doi:10.1038/nphys1222
    • Li, G.-W., Berg, O. G., and Elf, J. (2009). Effects of macromolecular crowding and dna looping on gene regulation kinetics. Nat. Phys. 5, 294-297. doi:10.1038/nphys1222.
    • (2009) Nat. Phys. , vol.5 , pp. 294-297
    • Li, G.-W.1    Berg, O.G.2    Elf, J.3
  • 21
    • 84877274846 scopus 로고    scopus 로고
    • Obstacles may facilitate and direct dna search by proteins
    • doi:10.1016/j.bpj.2013.03.030
    • Marcovitz, A., and Levy, Y. (2013). Obstacles may facilitate and direct dna search by proteins. Biophys. J. 104, 2042-2050. doi:10.1016/j.bpj.2013.03.030.
    • (2013) Biophys. J. , vol.104 , pp. 2042-2050
    • Marcovitz, A.1    Levy, Y.2
  • 22
    • 72149127671 scopus 로고    scopus 로고
    • How a protein searches for its site on DNA:the mechanism of facilitated diffusion
    • doi:10.1088/1751-8113/42/43/434013
    • Mirny, L., Slutsky, M., Wunderlich, Z., Tafvizi, A., Leith, J., and Kosmrlj, A. (2009). How a protein searches for its site on DNA:the mechanism of facilitated diffusion. J. Phys. A Math. Theor. 42:434013. doi:10.1088/1751-8113/42/43/434013.
    • (2009) J. Phys. A Math. Theor. , vol.42 , pp. 434013
    • Mirny, L.1    Slutsky, M.2    Wunderlich, Z.3    Tafvizi, A.4    Leith, J.5    Kosmrlj, A.6
  • 23
    • 84055217487 scopus 로고    scopus 로고
    • Effects of macromolecular crowding on genetic networks
    • doi:10.1016/j.bpj.2011.10.053
    • Morelli, M. J., Allen, R. J., and ten Wolde, P. R. (2011). Effects of macromolecular crowding on genetic networks. Biophys. J. 101, 2882-2891. doi:10.1016/j.bpj.2011.10.053.
    • (2011) Biophys. J. , vol.101 , pp. 2882-2891
    • Morelli, M.J.1    Allen, R.J.2    ten Wolde, P.R.3
  • 24
    • 77952002322 scopus 로고    scopus 로고
    • Theory of site-specific interactions of the combinatorial transcription factors with DNA
    • doi:10.1088/1751-8113/43/19/195003
    • Murugan, R. (2010). Theory of site-specific interactions of the combinatorial transcription factors with DNA. J. Phys. A Math. Theor. 43:195003. doi:10.1088/1751-8113/43/19/195003.
    • (2010) J. Phys. A Math. Theor. , vol.43 , pp. 195003
    • Murugan, R.1
  • 25
    • 20344389483 scopus 로고    scopus 로고
    • Models of stochastic gene expression
    • doi:10.1016/j.plrev.2005.03.003
    • Paulsson, J. (2005). Models of stochastic gene expression. Phys. Life Rev. 2, 157-175. doi:10.1016/j.plrev.2005.03.003.
    • (2005) Phys. Life Rev. , vol.2 , pp. 157-175
    • Paulsson, J.1
  • 26
    • 0014945567 scopus 로고
    • The lac represser-operator interaction:III
    • doi:10.1016/0022-2836(70)90074-4
    • Riggs, A. D., Bourgeois, S., and Cohn, M. (1970). The lac represser-operator interaction:III. kinetic studies. J. Mol. Biol. 53, 401-417. doi:10.1016/0022-2836(70)90074-4.
    • (1970) kinetic studies. J. Mol. Biol. , vol.53 , pp. 401-417
    • Riggs, A.D.1    Bourgeois, S.2    Cohn, M.3
  • 27
    • 31544443526 scopus 로고    scopus 로고
    • Escherichia coli k-12:a cooperatively developed annotation snapshot-2005
    • doi:10.1093/nar/gkj405
    • Riley, M., Abe, T., Arnaud, M. B., Berlyn, M. K., Blattner, F. R., Chaudhuri, R. R., et al. (2006). Escherichia coli k-12:a cooperatively developed annotation snapshot-2005. Nucleic Acids Res. 34, 1-9. doi:10.1093/nar/gkj405.
    • (2006) Nucleic Acids Res. , vol.34 , pp. 1-9
    • Riley, M.1    Abe, T.2    Arnaud, M.B.3    Berlyn, M.K.4    Blattner, F.R.5    Chaudhuri, R.R.6
  • 28
    • 15544371346 scopus 로고    scopus 로고
    • Gene regulation at the single-cell level
    • doi:10.1126/science.1106914
    • Rosenfeld, N., Young, J. W., Alon, U., Swain, P. S., and Elowitz, M. B. (2005). Gene regulation at the single-cell level. Science 307, 1962-1965. doi:10.1126/science.1106914.
    • (2005) Science , vol.307 , pp. 1962-1965
    • Rosenfeld, N.1    Young, J.W.2    Alon, U.3    Swain, P.S.4    Elowitz, M.B.5
  • 29
    • 0026771275 scopus 로고
    • Sliding and intermolecular transfer of the lac repressor:kinetic perturbation of a reaction intermediate by a distant dna sequence
    • doi:10.1073/pnas.89.11.4903
    • Ruusala, T., and Crothers, D. M. (1992). Sliding and intermolecular transfer of the lac repressor:kinetic perturbation of a reaction intermediate by a distant dna sequence. PNAS 89, 4903-4907. doi:10.1073/pnas.89.11.4903.
    • (1992) PNAS , vol.89 , pp. 4903-4907
    • Ruusala, T.1    Crothers, D.M.2
  • 30
    • 84861426505 scopus 로고    scopus 로고
    • Mode of regulation and the insulation of bacterial gene expression
    • doi:10.1016/j.molcel.2012.04.032
    • Sasson, V., Shachrai, I., Bren, A., Dekel, E., and Alon, U. (2012). Mode of regulation and the insulation of bacterial gene expression. Mol. Cell 46, 399-407. doi:10.1016/j.molcel.2012.04.032.
    • (2012) Mol. Cell , vol.46 , pp. 399-407
    • Sasson, V.1    Shachrai, I.2    Bren, A.3    Dekel, E.4    Alon, U.5
  • 31
    • 10044223573 scopus 로고    scopus 로고
    • Kinetics of protein-DNA interaction:facilitated target location in sequence-dependent potential
    • doi:10.1529/biophysj.104.050765
    • Slutsky, M., and Mirny, L. A. (2004). Kinetics of protein-DNA interaction:facilitated target location in sequence-dependent potential. Biophys. J. 87, 4021-4035. doi:10.1529/biophysj.104.050765.
    • (2004) Biophys. J. , vol.87 , pp. 4021-4035
    • Slutsky, M.1    Mirny, L.A.2
  • 32
    • 0034072450 scopus 로고    scopus 로고
    • DNA binding sites:representation and discovery
    • doi:10.1093/bioinformatics/16.1.16
    • Stormo, G. D. (2000). DNA binding sites:representation and discovery. Bioinformatics 16, 16-23. doi:10.1093/bioinformatics/16.1.16.
    • (2000) Bioinformatics , vol.16 , pp. 16-23
    • Stormo, G.D.1
  • 33
    • 0032032780 scopus 로고    scopus 로고
    • Specificity, free energy and information content in protein-DNA interactions
    • doi:10.1016/S0968-0004(98)01187-6
    • Stormo, G. D., and Fields, D. S. (1998). Specificity, free energy and information content in protein-DNA interactions. Trends Biochem. Sci. 23, 109-113. doi:10.1016/S0968-0004(98)01187-6.
    • (1998) Trends Biochem. Sci. , vol.23 , pp. 109-113
    • Stormo, G.D.1    Fields, D.S.2
  • 34
    • 33845442827 scopus 로고    scopus 로고
    • Diffusion of transcription factors can drastically enhance the noise in gene expression
    • doi:10.1529/biophysj.106.086157
    • van Zon, J. S., Morelli, M. J., Tanase-Nicola, S., and ten Wolde, P. R. (2006). Diffusion of transcription factors can drastically enhance the noise in gene expression. Biophys. J. 91, 4350-4367. doi:10.1529/biophysj.106.086157.
    • (2006) Biophys. J. , vol.91 , pp. 4350-4367
    • van Zon, J.S.1    Morelli, M.J.2    Tanase-Nicola, S.3    ten Wolde, P.R.4
  • 35
    • 77749239764 scopus 로고    scopus 로고
    • Quantitative study of synthetic hox transcription factor-dna interactions in live cells
    • doi:10.1073/pnas.0914612107
    • Vukojevic, V., Papadopoulos, D. K., Terenius, L., Gehring, W. J., and Rigler, R. (2010). Quantitative study of synthetic hox transcription factor-dna interactions in live cells. PNAS 107, 4093-4098. doi:10.1073/pnas.0914612107.
    • (2010) PNAS , vol.107 , pp. 4093-4098
    • Vukojevic, V.1    Papadopoulos, D.K.2    Terenius, L.3    Gehring, W.J.4    Rigler, R.5
  • 36
    • 84885391743 scopus 로고    scopus 로고
    • Stochastic Reaction-Diffusion Processes with Embedded Lower Dimensional Structures
    • Technical report, Department of Information Technology, Uppsala University.
    • Wang, S., Elf, J., Hellander, S., and Lotstedt, P. (2012). Stochastic Reaction-Diffusion Processes with Embedded Lower Dimensional Structures. Technical report, Department of Information Technology, Uppsala University.
    • (2012)
    • Wang, S.1    Elf, J.2    Hellander, S.3    Lotstedt, P.4
  • 37
    • 70350741354 scopus 로고    scopus 로고
    • An ensemble model of competitive multi-factor binding of the genome
    • doi:10.1101/gr.093450.109
    • Wasson, T., and Hartemink, A. J. (2009). An ensemble model of competitive multi-factor binding of the genome. Genome Res. 19, 2101-2112. doi:10.1101/gr.093450.109.
    • (2009) Genome Res. , vol.19 , pp. 2101-2112
    • Wasson, T.1    Hartemink, A.J.2
  • 38
    • 46349108554 scopus 로고    scopus 로고
    • Spatial effects on the speed and reliability of protein-DNA search
    • doi:10.1093/nar/gkn173
    • Wunderlich, Z., and Mirny, L. A. (2008). Spatial effects on the speed and reliability of protein-DNA search. Nucleic Acids Res. 36, 3570-3578. doi:10.1093/nar/gkn173.
    • (2008) Nucleic Acids Res. , vol.36 , pp. 3570-3578
    • Wunderlich, Z.1    Mirny, L.A.2
  • 39
    • 70349961774 scopus 로고    scopus 로고
    • Different gene regulation strategies revealed by analysis of binding motifs
    • doi:10.1016/j.tig.2009.08.003
    • Wunderlich, Z., and Mirny, L. A. (2009). Different gene regulation strategies revealed by analysis of binding motifs. Trends Genet. 25, 434-440. doi:10.1016/j.tig.2009.08.003.
    • (2009) Trends Genet. , vol.25 , pp. 434-440
    • Wunderlich, Z.1    Mirny, L.A.2
  • 40
    • 84865819662 scopus 로고    scopus 로고
    • System size reduction in stochastic simulations of the facilitated diffusion mechanism
    • doi:10.1186/1752-0509-6-121
    • Zabet, N. R. (2012). System size reduction in stochastic simulations of the facilitated diffusion mechanism. BMC Syst. Biol. 6:121. doi:10.1186/1752-0509-6-121.
    • (2012) BMC Syst. Biol. , vol.6 , pp. 121
    • Zabet, N.R.1
  • 41
    • 84861756737 scopus 로고    scopus 로고
    • A comprehensive computational model of facilitated diffusion in prokaryotes
    • doi:10.1093/bioinformatics/bts178
    • Zabet, N. R., and Adryan, B. (2012a). A comprehensive computational model of facilitated diffusion in prokaryotes. Bioinformatics 28, 1517-1524. doi:10.1093/bioinformatics/bts178.
    • (2012) Bioinformatics , vol.28 , pp. 1517-1524
    • Zabet, N.R.1    Adryan, B.2
  • 42
    • 84867364776 scopus 로고    scopus 로고
    • Computational models for large-scale simulations of facilitated diffusion
    • doi:10.1039/c2mb25201e
    • Zabet, N. R., and Adryan, B. (2012b). Computational models for large-scale simulations of facilitated diffusion. Mol. Biosyst. 8, 2815-2827. doi:10.1039/c2mb25201e.
    • (2012) Mol. Biosyst. , vol.8 , pp. 2815-2827
    • Zabet, N.R.1    Adryan, B.2
  • 43
    • 84860495813 scopus 로고    scopus 로고
    • GRiP:a computational tool to simulate transcription factor binding in prokaryotes
    • doi:10.1093/bioinformatics/bts132
    • Zabet, N. R., and Adryan, B. (2012c). GRiP:a computational tool to simulate transcription factor binding in prokaryotes. Bioinformatics 28, 1287-1289. doi:10.1093/bioinformatics/bts132.
    • (2012) Bioinformatics , vol.28 , pp. 1287-1289
    • Zabet, N.R.1    Adryan, B.2
  • 44
    • 77953170555 scopus 로고    scopus 로고
    • Computational limits to binary genes
    • doi:10.1098/rsif.2009.0474
    • Zabet, N. R., and Chu, D. F. (2010). Computational limits to binary genes. J. R. Soc. Interface 7, 945-954. doi:10.1098/rsif.2009.0474.
    • (2010) J. R. Soc. Interface , vol.7 , pp. 945-954
    • Zabet, N.R.1    Chu, D.F.2


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.