4204C Biochemical Sciences Building
440 Henry Mall
Madison WI 53706
Phone: (608) 262-6632
• B.S. 1979, University of Massachusetts
• Ph.D. 1987, University of Illinois (S. Kaplan)
• Postdoctoral, 1987-90, University of Wisconsin (W. Reznikoff)
• Shaw Scientist Award, 1992
• National Science Foundation Young Investigator Award, 1993
• Vilas Associate Award, 2004
• Fellow, American Academy of Microbiology, 2007
We are interested in the signaling pathways and gene expression programs organisms use to respond to changes in the levels of oxygen in the environment. Oxygen is essential for life of aerobic organisms but can also act as a poison by causing oxidative damage to proteins, lipids and DNA. Therefore, an organism's ability to respond efficiently and precisely to oxygen is critical to its survival.
Our approach is to focus on the mechanisms of key transcription factors in Escherichia coli that regulate this single-celled microbe's lifestyle in different oxygen environments. E. coli is an excellent model organism to investigate because of the rich history of study in this area, and because of the facile genomic, molecular genetic, biochemical and physiological approaches that can be exploited in this bacterium. Our findings also impact on understanding the integration of global regulatory networks with signal specific regulators to efficiently control gene expression in response to various inputs.
We are studying two transcription factors, IscR and FNR, that exploit Fe-S metal centers in the global response to oxygen. FNR contains an oxygen labile [4Fe-4S] cluster and functions as an oxygen sensor. IscR contains a [2Fe-2S] cluster and senses Fe-S cluster availability via cluster synthesis. Our results indicate that the properties of Fe-S proteins enable exquisite control of their function as transcription factors.
We are also discovering how these transcription factors reprogram gene expression to allow E. coli to adapt to oxygen limiting environments similar to that found in the gut, which is an important habitat of this bacterium. We have used global gene expression profiling (microarrays) to uncover the roles of IscR and FNR in controlling transcription under these conditions. As expected, we found that E. coli responds to oxygen deprivation by synthesizing proteins that provide alternate mechanisms for conserving energy when oxygen is not available. However, we also discovered new functions that are upregulated under anaerobic conditions and we hypothesize that these contribute in a novel way to anaerobic growth.
Perform a customized PubMed literature search for Dr. Kiley.
• Mettert EL, Kiley PJ. Coordinate regulation of the Suf and Isc Fe-S cluster
biogenesis pathways by IscR is essential for viability of Escherichia coli. J
Bacteriol. 2014 Dec;196(24):4315-23. doi: 10.1128/JB.01975-14. Epub 2014 Sep 29.
PubMed PMID: 25266384; PubMed Central PMCID: PMC4248859.
• Park DM, Kiley PJ. The influence of repressor DNA binding site architecture on
transcriptional control. MBio. 2014 Aug 26;5(5):e01684-14. doi:
10.1128/mBio.01684-14. PubMed PMID: 25161193; PubMed Central PMCID: PMC4173790.
• Miller HK, Kwuan L, Schwiesow L, Bernick DL, Mettert E, Ramirez HA, Ragle JM,
Chan PP, Kiley PJ, Lowe TM, Auerbuch V. IscR is essential for Yersinia
pseudotuberculosis type III secretion and virulence. PLoS Pathog. 2014 Jun
12;10(6):e1004194. doi: 10.1371/journal.ppat.1004194. eCollection 2014 Jun.
PubMed PMID: 24945271; PubMed Central PMCID: PMC4055776.
• Park DM, Akhtar MS, Ansari AZ, Landick R, Kiley PJ. The bacterial response
regulator ArcA uses a diverse binding site architecture to regulate carbon
oxidation globally. PLoS Genet. 2013;9(10):e1003839. doi:
10.1371/journal.pgen.1003839. Epub 2013 Oct 17. PubMed PMID: 24146625; PubMed
Central PMCID: PMC3798270.
• Myers KS, Yan H, Ong IM, Chung D, Liang K, Tran F, KeleÅŸ S, Landick R, Kiley
PJ. Genome-scale analysis of Escherichia coli FNR reveals complex features of
transcription factor binding. PLoS Genet. 2013 Jun;9(6):e1003565. doi:
10.1371/journal.pgen.1003565. Epub 2013 Jun 20. PubMed PMID: 23818864; PubMed
Central PMCID: PMC3688515.
• Rajagopalan S, Teter SJ, Zwart PH, Brennan RG, Phillips KJ, Kiley PJ. Studies
of IscR reveal a unique mechanism for metal-dependent regulation of DNA binding
specificity. Nat Struct Mol Biol. 2013 Jun;20(6):740-7. doi: 10.1038/nsmb.2568.
Epub 2013 May 5. PubMed PMID: 23644595; PubMed Central PMCID: PMC3676455.
• Giel JL, Nesbit AD, Mettert EL, Fleischhacker AS, Wanta BT, Kiley PJ.
Regulation of iron-sulphur cluster homeostasis through transcriptional control of
the Isc pathway by [2Fe-2S]-IscR in Escherichia coli. Mol Microbiol. 2013
Feb;87(3):478-92. doi: 10.1111/mmi.12052. Epub 2012 Oct 17. PubMed PMID:
23075318; PubMed Central PMCID: PMC4108476.
• Nesbit AD, Fleischhacker AS, Teter SJ, Kiley PJ. ArcA and AppY antagonize IscR
repression of hydrogenase-1 expression under anaerobic conditions, revealing a
novel mode of O2 regulation of gene expression in Escherichia coli. J Bacteriol.
2012 Dec;194(24):6892-9. doi: 10.1128/JB.01757-12. Epub 2012 Oct 12. PubMed PMID:
23065979; PubMed Central PMCID: PMC3510566.
• Fleischhacker AS, Stubna A, Hsueh KL, Guo Y, Teter SJ, Rose JC, Brunold TC,
Markley JL, Munck E, Kiley PJ. Characterization of the [2Fe-2S] cluster of
Escherichia coli transcription factor IscR. Biochemistry. 2012 Jun
5;51(22):4453-62. Epub 2012 May 24. PubMed PMID: 22583201; PubMed Central PMCID:
• Mettert EL, Kiley PJ. Fe-S proteins that regulate gene expression. Biochim
Biophys Acta. 2014 Nov 20. pii: S0167-4889(14)00416-9. doi:
10.1016/j.bbamcr.2014.11.018. [Epub ahead of print] Review. PubMed PMID:
• Dietrich LE, Kiley PJ. A shared mechanism of SoxR activation by redox-cycling
compounds. Mol Microbiol. 2011 Mar;79(5):1119-22. doi:
10.1111/j.1365-2958.2011.07552.x. Epub 2011 Jan 31. PubMed PMID: 21338412.
• Fleischhacker AS, Kiley PJ. Iron-containing transcription factors and their
roles as sensors. Curr Opin Chem Biol. 2011 Apr;15(2):335-41. doi:
10.1016/j.cbpa.2011.01.006. Epub 2011 Feb 1. Review. PubMed PMID: 21292540;
PubMed Central PMCID: PMC3074041.