JOURNAL OF BACTERIOLOGY, Sept. 2006, p. 6709–6713 0021-9193/06/$08.00⫹0 doi:10.1128/JB.00680-06 Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Vol. 188, No. 18
Transcriptional Response of Escherichia coli to TPEN Tara K. Sigdel, J. Allen Easton, and Michael W. Crowder* Department of Chemistry and Biochemistry, 160 Hughes Hall, Miami University, Oxford, Ohio 45056 Received 12 May 2006/Accepted 4 July 2006
DNA microarrays were used to probe the transcriptional response of Escherichia coli to N, N, Nⴕ, Nⴕ-tetrakis(2pyridylmethyl)ethylenediamine (TPEN). Fifty-five transcripts were significantly up-regulated, including all of the genes that are regulated by Zur and many that are regulated by Fur. In the same TPEN-treated cells, 46 transcripts were significantly down-regulated. mented cultures are transcriptionally regulated by Fur, the iron uptake regulator (Table 1), and several are involved in Fe transport. The genes (entB, entA, entD, entE, and fes) which encode proteins involved with enterobactin synthesis and uptake (26, 29, 54) and the fec genes (fecR and fecI), which encode proteins involved in Fe import (23), were significantly up-regulated. Several other genes (fhuA, exbB, exbD, fhuD, fhuC, and fhuF) associated with ferrichrome transport in E. coli were also up-regulated (19, 56, 62). Forty-six transcripts were significantly down-regulated in E. coli cells stressed with TPEN (Table 2). Two operons in E. coli, flgBCDEFGHIJKL and flgAMN, possess genes that encode proteins involved in flagellar biosynthesis (8). Some of these motility-related genes, namely, flgB, fliM, and motB, were previously reported as being up-regulated in E. coli cells stressed with excess Zn(II) (51). In addition, the expression of flagellar biosynthetic proteins in E. coli is affected by the concentration of copper, possibly exerting its effect via the OmpR or H-NS transcriptional regulators (42). All of the genes in the cus and cue systems, which confer copper tolerance to E. coli (68), were also down-regulated, although cusA and copA were filtered out of the data shown in Table 2. Previous studies have demonstrated that the expression levels of the cus and cue genes are dependent on aerobic/anaerobic conditions as well as on the levels of copper in the periplasm/cytoplasm (68). The expression levels of cytoplasmic ferritin (3) were also significantly down-regulated in TPEN-treated cells. To validate the microarray data, two representative genes were selected for real-time PCR and assayed for the level of mRNA by a two-step, real-time PCR technique. The genes yodA and pdxH, which were up-regulated (21-fold) and exhibited no change (1.1-fold), respectively, were analyzed with realtime PCR. Real-time PCR results were as follows: yodA upregulated, 17 ⫾ 1; pdxH up-regulated, 1.1 ⫾ 0.1. In order to probe whether the changes observed in cells grown in the presence of TPEN were due to the chelator, RT-PCR was used to probe for the expression levels of yodA in E. coli cells grown in minimal medium containing 5 M TPEN and 30 M Zn(II). There was no change in transcript levels of yodA when E. coli was cultured in this medium. Despite the fact that TPEN is often referred to as a Zn(II)specific chelator (17, 33, 38, 48, 59, 64, 71, 79, 80, 83, 88), the analyses of our microarray data suggest that the levels of other metal ions may have been affected by the presence of TPEN.
* Corresponding author. Mailing address: Department of Chemistry and Biochemistry, 160 Hughes Hall, Miami University, Oxford, OH 45056. Phone: (513) 529-7274. Fax: (513) 529-5715. E-mail: crowdemw @muohio.edu. 6709
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The transcriptional response of Escherichia coli to elevated levels of metal ions such as Zn(II), Cd(II), Co(II), Ni(II), and Fe(II) has been probed in an effort to understand the mechanisms by which the homeostatic levels of these metal ions are maintained (10, 15, 51, 95, 96). In contrast, very few studies have probed the global response of E. coli to low levels of metal ions, presumably due to the difficulty of sufficiently depleting the growth medium of metal ions. In this study, cDNA microarrays were used to probe the transcriptional response of E. coli to stress by N, N, N⬘, N⬘-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). TPEN (58, 81), a cell-permeative, divalent metal chelator, is often called “Zn(II) specific” (17, 33, 38, 48, 59, 64, 71, 79, 80, 83, 88). Our data show significant changes in the transcription of several genes in cells stressed with TPEN. To identify genes that are differentially expressed in response to TPEN, E. coli BL21(DE3) cells were grown in minimal medium (76) until the cultures reached mid-log phase. TPEN was introduced, and the cells were cultured for 5 h; this time was chosen so that the results would correspond to previous transcriptional response studies with excess Zn(II) (51). The cultures containing 5 M TPEN were analyzed with DNA microarrays (E. coli K12 V2 array slides from MWGBIOTECH), and the results were compared to those from E. coli cells grown in minimal medium containing no TPEN. A minimum of six slides was used for each experiment (three slides with one combination of Cy3 and Cy5 dyes and three slides with swapped dyes). Fifty-five transcripts were significantly up-regulated (twofold) (Table 1). Four genes (ykgM, znuA, znuC, and yodA) that are regulated by Zur, the Zn(II) uptake regulator (30), exhibited significant increases in expression. The remaining Zur-regulated transcript, znuB, was also up-regulated; however, this transcript did not meet our filtering criteria: (i) P values of ⱕ0.5, (ii) ⱖ2-fold changes in expression, and (iii) consistent data in all six slides. The expression of zntA, which is regulated by ZntR and encodes the high-affinity Zn(II) exporter in E. coli (7, 14, 78), was unchanged in E. coli cultures stressed with TPEN (see the complete set of DNA array data). Twenty-nine of the up-regulated genes from TPEN-supple-
J. BACTERIOL. TABLE 1. Genes up-regulated in E. coli cells stressed with TPEN IDa
B0296 B1973 B1857 B1858
ykgM yodA znuA znuC
23 21 7.6 2.2
5.5E-04 2.8E-03 1.5E-03 1.1E-02
Ribosomal protein; L31 paralog Cd(II) induced; putative Zn(II) transporter Periplasmic component of Zn(II)-specific ZnuABC transporter ATPase of ZnuABC
70 21, 75 73 73
B2673 B2674 B0595 B0596 B0583 B3006 B3005 B0594 B1683 B1682
nrdH nrdI entB entA entD exbB exbD entE sufB sufC
12 12 9.7 8.7 7.2 5.8 5.3 5.1 5.1 5.1
1.9E-04 8.8E-03 2.4E-05 6.1E-03 1.0E-04 4.9E-04 1.3E-03 1.6E-02 3.6E-03 4.2E-03
39 39 26 91 26 34 34 26 69 69
B0151 B4292 B4293 B0585 B1102 B0150 B4367 B1679 B1252 B1681 B1680 B2676 B3908 B4290 B2155 B0153 B0592 B1132 B0586
fhuC fecR fecI fes fhuE fhuA fhuF sufE tonB ynhC sufS nrdF sodA fecB cirA fhuB fepB ycfC entF
5.1 4.9 4.8 4.5 4.4 4.3 2.10 2.01 3.9 3.9 3.7 3.1 3.0 3.0 2.9 2.9 2.7 2.6 2.4
1.1E-03 2.4E-03 4.5E-03 1.9E-02 3.4E-03 1.9E-03 4.7E-03 1.4E-03 5.2E-04 3.5E-03 6.7E-03 8.7E-04 2.0E-02 4.4E-02 3.3E-03 5.0E-02 2.2E-02 2.1E-02 2.5E-02
Glutaredoxin-like protein Stimulates NrdH 2,3-Dihydro-2,3-dihydroxybenzoate synthetase 2,3-Dihydro-2,3-dihydroxybenzoate dehydrogenase Enterochelin synthetase, component D Uptake of enterochelin; TonB-dependent uptake of b colicins Enterochelin synthetase, component d 2,3-Dihydroxybenzoate-AMP ligase Component of SufBCD cysteine desulfurase activator complex ATP-binding component of SufBCD cysteine desulfurase activator complex ATP-binding component of hydroxymate-dependent iron transport Regulator for fec operon, periplasmic Probable RNA polymerase sigma factor Enterochelin esterase Outer membrane receptor for ferric iron uptake Outer membrane protein receptor for ferrichrome, colicin m Ferrioxamine B reductase Cysteine desulfurase TonB Component of SufBCD cysteine desulfurase activator complex L-Selenocysteine lyase Subunit of ribonucleoside-diphosphate reductase II Mn superoxide dismutase Periplasmic component of iron dicitrate ABC transporter Outer membrane receptor for colicin I receptor Component of Fe(III) hydroxamate ABC transporter Fe(III) enterobactin ABC transporter Membrane protein in operon with purB Apo-serine activating enzyme
16 22 4 13 11 24 62 55 45 69 72 46 36 31 12 16 84 28 26
B1611 B2962 B2963 B2237 B3924
fumC yggX mltC inaA fpr
3.8 3.2 2.6 2.2 2.1
2.6E-02 6.4E-03 4.6E-05 3.1E-03 4.8E-02
Class II fumarase Protects Fe-S clusters from oxidation Component of lytic murein transglycosylase C pH-inducible protein involved in stress response Flavodoxin NADP⫹ reductase
89 67 6 93 9
Other stress related
B0126 B1053 B0313 B1629 B4062 B1307
yadF yceE betI rsxC soxS pspD
3.7 2.5 2.4 2.1 2.1 2.0
6.9E-03 1.3E-03 5.9E-03 2.9E-02 7.3E-03 3.4E-02
Carbonic anhydrase Drug resistance protein Transcription repressor of bet genes Component of SoxR reducing complex Superoxide response regulon Phage shock protein
60 65 49 47 52 61
B1264 B3161 B1265 B2678 B0311 B4245 B2028 B1261 B3409 B1981 B0931
trpE mtr trpL proW betA pyrB ugd trpB feoB shiA pncB
5.3 2.9 2.7 2.6 2.6 2.6 2.4 2.3 2.3 2.3 2.0
3.7E-02 7.6E-04 3.1E-02 2.4E-02 3.1E-03 2.1E-02 3.1E-03 5.0E-02 1.7E-02 4.7E-02 7.3E-03
Anthranilate synthase component I Trp transport protein Trp operon leader peptide Pro and Gly betaine transporter Choline dehydrogenase Aspartate transcarbamoylase UDP-glucose-6-dehydrogenase Trp synthase ␤ Fe(II) transport protein Shikimate transporter Nicotinate phosphoribosyltransferase
20 32 43 5 77 41 85 44 40 92 94
TPEN has been reported to bind Cd(II) (Kd ⫽ 4.7 ⫻ 10⫺17), Co(II) (Kd ⫽ 2.6 ⫻ 10⫺17), Ni(II) (Kd ⫽ 2.8 ⫻ 10⫺22), and Cu(II) (Kd ⫽ 2.9 ⫻ 10⫺21) more tightly than it binds Zn(II) (2). In addition, TPEN forms stable complexes with Fe(II) (Kd ⫽
2.5 ⫻ 10⫺15) (2). Since TPEN forms much tighter complexes with Cu(II), it is likely that the down-regulation of the copper homeostasis/export transcripts, cueO, copA, cusA, cusB, cusC, and cusF, is due to low levels of intracellular copper. Twenty-
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VOL. 188, 2006
TABLE 2. Genes down-regulated in E. coli cells stressed with TPEN Decrease (fold)
flgC flgD flgG flgI flgH flgF flgJ flgB flgA flgK flgM
7.9 7.5 4.9 4.3 4.0 3.9 3.9 3.8 3.4 3.1 2.3
3.1E-05 3.6E-04 1.2E-05 3.3E-04 8.7E-03 5.4E-05 2.8E-03 3.8E-04 4.7E-02 2.6E-02 3.6E-03
Cell-proximal portion of basal-body rod Initiator of hook assembly Cell-distal portion of basal-body rod p ring of flagellar basal body Outer membrane ring protein Cell-proximal portion of basal-body rod Flagellar protein Cell proximal portion of basal-body rod Assembly of basal-body p ring Hook filament junction protein Anti-flia factor
8 8 8 8 8 8 8 8 8 8 8
B2094 B2095 B2092 B2091 B2167 B2093 B2169 B2168 B2096 B4034 B3417 B1198 B1817
gatA gatZ gatC gatD fruA gatB fruB fruK gatY malE malP ycgC manX
6.4 5.3 4.9 4.7 4.0 3.7 3.5 3.2 2.6 2.4 2.3 2.3 2.1
5.9E-03 5.6E-03 2.7E-02 2.4E-03 2.2E-03 1.3E-02 3.1E-03 2.8E-02 1.7E-02 8.1E-03 5.0E-03 6.5E-03 1.5E-03
Enzyme IIa of PTS Putative tagatose 6-phosphate kinase Enzyme IIc of PTS Galactitol-1-phosphate dehydrogenase Fructose specific transporter Enzyme IIb of PTS Fructose specific IIa component Fructose 1-phosphate kinase Tagatose-bisphosphate aldolase Maltose binding protein Maltodextrin phosphorylase Dihydroxyacetone kinase M Mannose transporter
66 66 66 66 66 66 66 66 66 66 66 66 66
Fe and Cu metabolism
B1905 B0123 B0573 B0572 B0574
ftnA yacK ylcC ylcB ylcD
5.3 2.5 2.5 2.4 2.2
3.8E-04 2.7E-03 2.7E-03 2.0E-02 1.4E-02
Cytoplasmic ferritin CueO, Cu(I) oxidase CusF, copper efflux CusC, copper efflux CusB, copper efflux
82 27 27 27 27
B1656 B1379 B3687
sodB hslJ ibpA
3.7 2.3 2.1
2.0E-03 7.4E-03 4.7E-03
Fe superoxide dismutase Heat shock protein Heat shock protein
36 53 50
B3936 B2142 B2286 B0972 B4116 B0411 B1380 B3209 B0651 B1245 B0872 B1241
rpmE yohK nuoC hyaA adiY tsx ldhA yhbL ybeK oppC hcr adhE
3.4 2.5 2.5 2.5 2.4 2.3 2.3 2.3 2.3 2.2 2.2 2.0
2.2E-02 3.0E-02 1.3E-02 4.8E-02 2.8E-02 2.8E-2 1.1E-02 1.8E-02 1.9E-2 7.2E-3 4.0E-02 2.1E-03
63 43 25 37 86 57 18 35 74 87 90 18
L31 ribosomal protein Serotonin transporter Component of NADH dehydrogenase Hydrogenase small subunit Transcription activator of Arg decarboxylase Nucleoside channel Lactate dehydrogenase Isoprenoid biosynthesis protein Ribonucleoside hydrolase ABC transporter for peptides NADH oxidoreductase Acetaldehyde dehydrogenase and Fe-dependent alcohol dehydrogenase ABC transporter for peptides NADH dehydrogenase
B1074 B1075 B1078 B1080 B1079 B1077 B1081 B1073 B1072 B1082 B1071
PTS, phosphotransferase system. ID, identifier.
nine Fur-regulated transcripts were up-regulated. Despite the fact that Fe(II) binds 1 order of magnitude less tightly to TPEN than Zn(II) (2), it is possible that TPEN lowered the intracellular concentrations of Fe(II), resulting in the transcription of Fur-regulated iron uptake proteins. The reduction in intracellular concentrations of Fe(II) could be due to direct chelation by TPEN or by oxidation of intracellular Fe(II) to Fe(III). The fact that several other SoxRS-regulated transcripts were up-regulated in cultures stressed with TPEN (Table 1) suggests oxidative stress in these cells (97). It is also
possible that the reduction of intracellular Zn(II) caused by the presence of TPEN resulted in an improperly folded Fur, which requires one Zn(II) for proper structure/function (1). Taken together, these results strongly suggest that the intracellular levels of several metal ions in E. coli can be affected by TPEN, which indicates that caution should be exercised when TPEN is used in experiments to control intracellular concentrations of Zn(II) in cells. Microarray data accession number. The microarray data have been loaded into the Gene Expression Omnibus (GEO)
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with the accession number GSE5356 (www.ncbi.nlm.nih.gov /geo). We thank Paul Christopher Wood and Maria Lia Molas from the Center for Bioinformatics and Functional Genomics (CBFG) for helping with the microarray scanner and real-time PCR experiments. We are also grateful to Herbert Auer, Director of the Affymetrix Core, Columbus Children’s Research Institute, for training and assistance in the analysis of cDNA microarray data. We acknowledge Miami University (Committee on Faculty Research and OARS) and the National Institutes of Health (GM079411) for funding this work.
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