Dr. Nancy P. Keller

Research Interest

Fungal molecular biology, mycotoxins, and fungal genomics.

Research Description

The long-term goal of my research program is to reduce aflatoxin and sterigmatocystin contamination of food and feed crops. Aflatoxin (AF) and sterigmatocystin (ST) are toxic and carcinogenic secondary metabolites produced by the same biochemical pathway in several Aspergillus spp. My program focuses on identifying the molecular genetic processes controlling expression of ST/AF biosynthesis and host metabolites which effect fungal growth and ST/AF biosynthesis. Results from these areas of research are directed towards designing rational ST/AF control strategies and should contribute to control of other fungal pathogens.

We are using A. nidulans to dissect the molecular mechanisms governing genetic control of ST biosynthesis. We have isolated a ST gene cluster in A. nidulans and have identified gene functions within the cluster through gene disruption and sequence analysis. This cluster contains 26 genes encoding both enzymatic activities and regulatory proteins necessary for ST and AF biosynthesis. We have demonstrated that both regulatory and structural genes are conserved between the A. nidulans ST gene cluster and the A. flavus and A. parasiticus AF gene clusters. Most interestingly, we find that both sporulation and mycotoxin biosynthesis are inactivated by the same Ga protein-dependent signaling pathway thus suggesting the possibility of a strategy to control inoculum and ST/AF production simultaneously.

We are also interested in host factors which affect the regulation of mycotoxin production in Aspergillus spp. and have identified linoleic acid-derived compounds from the lipoxygenase pathway of plants which regulate both fungal sporulation and ST/AF production. One current goal involves transforming corn and peanut plants with a soybean lipoxygenase gene whose product inhibited AF/ST biosynthesis in laboratory studies. Ultimately, many of our studies should lead to creating transgenic crops where AF/ST-inducing or inhibiting traits will be engineered 'out' or 'into' plants respectively.

These studies will be complemented by functional genomic projects where we are involved in sequencing the Aspergillus genome and analyzing Aspergillus/seed ESTs. Microarray analysis of host seed and Aspergillus genes should reveal those set required for pathogenesis and aflatoxin production in situ.

Graduate Students

Saori Amaike
JeeHwan Oh
Jonathan Palmer
Mona Shaaban

Postdoctoral Fellows

Taylor Dagenais
Graeme Garvey

Academic Research Staff

Jin Woo Bok
Marisa Trapp

Selected Publications – NCBI PubMed search for "N. P. Keller"

Gao X, Brodhagen M, Isakeit T, Horowitz-Brown S, Göbel C, Betran J, Feussner I, Keller NP, Kolomiets MV. (accepted) Inactivation of the lipoxygenase ZmLOX3 increases susceptibility of maize to Aspergillus spp Mol Plant Microbe Interact (in press)

Palmer JM, Perrin RM, Dagenais TR, Keller NP. (2008) H3K9 methylation regulates growth and development in Aspergillus fumigatus. Eukaryot Cell. Oct 10. [Epub ahead of print]

Horowitz Brown S, Zarnowski R, Sharpee WC, Keller NP. (2008)Morphological transitions governed by density dependence and lipoxygenase activity in Aspergillus flavus. Appl Environ Microbiol. 74:5674-85.

Kale S, Milde L, Trapp M, Frisvad J, Keller NP, Bok JW. (2008) Requirement of LaeA for Secondary Metabolism and Sclerotial Production in Aspergillus flavus. Fungal Genetics Biology. 45:1422-9

Dagenais T, Chung D, Giles S, Hull, C, Andes D, Keller NP. (2008) Abberancies in conidiophore development and conidial/macrophage interactions in a dioxygenase mutant of Aspergillus fumigatus. Infect Immun 76:3214-20

Bayram O, Krappmann S, Ni M, Bok JW, Helmstaedt K, Valerius O, Braus-Stromeyer S, Kwon NJ, Keller NP, Yu JH, Braus GH. (2008) VelB/VeA/LaeA coordinate light information, fungal development and secondary metabolism. Science 320:1504-6

Hammond, T.M., Andrewski, M.D., Roossinck, M. and Keller N.P. (2008) Aspergillus mycoviruses are targets and suppressors of RNA silencing. Euk Cell. 2007 Dec 7. (Epub ahead of print)

Brodhagen, M., Tsitsigiannis, D., Hornung, E., Goebel, C., Feussner, I. and Keller, N.P. (2008) Reciprocal oxylipin-mediated cross talk in the Aspergillusseed pathosystem. Mol Microbiol. 67:378-391.

Shwab, E., Bok, J.W., Tribus, M., Galehr, J., Graessle, S. and Keller, N.P. (2007) Histone deacetylase activity regulates chemical diversity in Aspergillus. Euk Cell. 6:1656-64.

Perrin, R.M., Fedorova, N.D., Bok, J.W., Cramer, R.A., Wortman, J.R., Kim, H.S., Nierman, W.C. and Keller, N.P. (2007) Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PloS Pathogens. Apr:3(4):e50.

Bok, J.W., Noordermeer, D., Kale, S.P. and Keller, N.P. (2006) Secondary metabolic gene cluster silencing in Aspergillus nidulans. Mol Microbiol. 61:1636-1645.

Bok J.W., Balajee S. A., Marr K. A., Andes D., Fog Nielsen K., Frisvad J. C., Keller N. P. (2005) LaeA, a regulator of virulence determinants in Aspergillus fumigatus. Euk Cell: in press.

Tsitsigiannis D. I., Kunze S, Willis D K, Feussner I, Keller NP. (2005) Aspergillus infection inhibits the expression of peanut 13S-HPODE-forming seed lipoxygenases. Mol Plant Microbe Interactions: in press.

Tsitsigiannis D. I., Koweiski, T., Zarnowski R., Keller N.P. (2005) Three putative oxylipin biosynthetic genes integrate sexual and asexual development in Aspergillus nidulans. Microbiology 151:1809-21.

Maggio-Hall L., Wilson R., Keller N. P. (2005) Fundamental contribution of b-oxidation to polyketide mycotoxin production in planta. Mol Plant Microbe Interactions: in press.

Tsitsigiannis D. I., Bok J.-W., Andes D., Fog Nielsen K., Frisvad J. C., Keller N. P. (2005) Aspergillus cyclooxygenase-like enzymes are associated with prostaglandin production and virulence. Infect Immunol: in press.

Hammond TM, Keller NP. (2005) RNA silencing in Aspergillus nidulans is independent of RNA dependent RNA polymerases. Genetics 169: 607-17.

McDonald T., Brown D., Keller N. P., Hammond T. (2005) Inverted Repeat Transgenes Silence Mycotoxin Production in Aspergillus and Fusarium species. Mol Plant Microbe Interactions 18:539-545.

Chang, P.-K., Wilson, R. A., Keller, N. P., Cleveland, T. E. (2004) Deletion of the D12-oleic acid desaturase gene of a non-aflatoxigenic Aspergillus parasiticus field isolate affects conidiation and sclerotial development . J Appl Micro 97:1178-1184.

Tsitsigiannis D. I., Koweiski, T., Zarnowski R., Keller N.P. (2004) Endogenous lipogenic regulators of spore balance in Aspergillus nidulans. Euk Cell 3: 1398-411.

Maggio-Hall, L. and Keller N. P. (2004) Mitochondrial _-oxidation in Aspergillus nidulans. Mol Microbiol 54: 1173-85.

Wilkinson H, Ramaswamy A, Sim S, and Keller NP. (2004) Increased conidiation associated with progression along the sterigmatocystin biosynthetic pathway Mycologia. 96: 1190-1198.

Wilson, R. A, Calvo, A. M., Chang P.-K., Keller N.P. (2004) Characterization of the Aspergillus parasiticus D12-desaturase gene: a role for lipid metabolism in the Aspergillus/ seed interaction. Microbiology 150:2881-2888.

Roze LV, Beaudry RM, Keller NP, Linz JE. (2004) Regulation of aflatoxin synthesis by FadA/cAMP/protein kinase A signaling in Aspergillus parasiticus. Mycopathologia 158:219-32.

Calvo A M, Bok J.-W., Brook W, Keller NP. (2004) ApveA genetically links toxin and sclerotial production in Aspergillus parasiticus. Appl Environ Microbiol 70:4733-9.

Zhang Y-Q, Brock M, Keller N P. (2004) Connection of propionyl-CoA metabolism to polyketide biosynthesis in Aspergillus nidulans. Genetics: 168:785-794.

Tsitsigiannis D. I., Zarnowski R., Keller N.P. (2004) The Lipid Body Protein, PpoA, Coordinates Sexual and Asexual Sporulation in Aspergillus nidulans. J Biol Chem 279:11344-53.

Wilson R A, Chang P.-K., Dobrzyn A., Ntambi J. A., Zarnowski R., Keller N.P. (2004) Two D9-stearic acid desaturases are required for Aspergillus nidulans growth and development. Fung Genet Biol 41:501-9.

Bok J-W, Keller N P. (2004) LaeA, a regulator of secondary metabolism in Aspergillus Eukaryotic Cell 3: 527-535.

Zhang Y-Q, Keller N P. (2004) Blockage of 2-methylcitrate cycle inhibits polyketide production in Aspergillus nidulans. Mol Microbiol 52:541-550.

McDonald T, Devi T, Shimizu K, Sim S-C, Keller NP (2004) Signaling events connecting mycotoxin biosynthesis and sporulation in Aspergillus and Fusarium spp. In New Horizon of Mycotoxicology for Assuring Food Safety, Proceedings of the International Symposium of Mycotoxicology (Editor: Takumi Yoshizawa) pp 139-147.

Shimizu K, Hicks J, Huang T.-P, Keller N P (2003) Pka, Ras and RGS protein interactions regulate activity of AflR, a Zn(II)2Cys6 transcription factor in Aspergillus nidulans Genetics 165:1095-1104.

Greene A, Keller N, Hass H, Bell-Pedersen D. (2003) A FRQ-less circadian oscillator in Aspergillus spp. regulates daily sclerotial production and gene expression Eukaryotic Cell 2:231-237.

Calvo A, Wilson R, Bok J, Keller NP. (2002) Relationship between secondary metabolism and fungal development. Mol Microbiol Reviews. 66:447-459.

Yuan J, Bok J, Guzman-de-Peña D, Keller NP. (2002) Requirement of spermidine for developmental transitions in Aspergillus nidulans. Mol Microbiol 46:801-812.

Fillinger S, Chaveroche M-K, Shimizu K, Keller N, d'Enfert C (2002) cAMP and ras signaling independently control spore germination in the filamentous fungus Aspergillus nidulans. Mol Microbiol 44:1001-1016.

Wilson R A, Gardner H W, Keller N P (2001) Cultivar-dependent expression of a maize lipoxygenase responsive to seed infesting fungi. Mol Plant Microbe Inter 14:980-987.

Calvo A, Gardner H W, Keller N P (2001) Genetic connection between fatty acid metabolism and sporulation in Aspergillus nidulans. J Biol Chem 276:25766-25774.

Klich M, Mendoza C, Mullaney E, Keller N, Bennett J (2001) A new sterigmatoycstin-producing Emericella taxon from agricultural desert soils. Sys Appl Microbiol 24:131-138.

Hicks J, Lockington R A, Strauss J, Dieringer D, Kubicek C, Kelly J, Keller N (2001) RcoA has pleiotropic effects on Aspergillus nidulans cellular developmental. Mol Microbiol in press.

Shimizu K., Keller N. P. (2001) Genetic involvement of a cAMP-dependent protein kinase in a G protein signaling pathway regulating morphological and chemical transitions in Aspergillus nidulans Genetics157: 591-600.

Tag A, Hicks J, Garifullina G, Beremand M, Keller N (2000) G-protein signaling mediates differential production of toxic secondary metabolites. Mol Microbiol 38:658-665.

Keller N P, Watanabe C, Kelkar H, Adams T H, Townsend C (2000) Requirement of monooxygenase-mediated steps for sterigmatocystin biosynthesis by Aspergillus nidulans. Appl Environ Microbiol. 66:359-362.

Burow G B, Gardner H W, Keller N P (2000) Characterization of an Aspergillus responsive peanut seed lipoxygenase. Plant Mol Biol 42:689-701.

Calvo A, Hinze L, Gardner H W, Keller N P (1999) Sporogenic effect of polyunsaturated fatty acids on Aspergillus spp. development. Appl Environ Microbiol 65:3668-3673.

Butchko R A E, Adams T H, Keller N P (1999) Aspergillus nidulans mutants defective in stc gene cluster regulation. Genetics 153:715-20.

Fernandes M, Keller N P, Adams T. (1998) Sequence-specific binding by Aspergillus nidulans AflR, a C6 zinc cluster protein regulating mycotoxin biosynthesis. Mol Microbiol 28:1355-1365.

Hicks J K, Yu J-H, Keller N P, Adams T H. (1997) Aspergillus sporulation and mycotoxin production both require inactivation of the FadA Ga protein-dependent signaling pathway. EMBO J. 16:4916-4923.

Burow G B, Nesbitt T C, Dunlap J D, Keller N P. (1997) Seed lipoxygenase products modulate Aspergillus mycotoxin biosynthesis. Mol Plant Microbe Inter 10:380-387.

Kelkar H S, Schloss T W, Haw J, Keller N P, Adams T H. (1997) Aspergillus nidulans stcL encodes a putative P-450 monooxygenase required for bisfuran desaturation during aflatoxin/sterigmatocystin biosynthesis. J Biol Chem 272:1589-1594.

Brown D W, Adams T H, Keller N P. (1996) A fatty acid synthase required for secondary metabolism. PNAS 93:14873-14877.

Yu J, Butchko R A E, Fernandes M, Keller N P, Leonard T, Adams T (1996) Conservation of structure and function of the aflatoxin regulatory gene aflR from Aspergillus nidulans and A. flavus. Curr Gene 29:549-555.

Brown D W, Yu J-H, Kelkar H, Fernandes M, Nesbitt T C, Keller N P, Adams T H, Leonard T J. (1996) Twenty-five co-regulated transcripts define the sterigmatocystin gene cluster in Aspergillus nidulans. PNAS 93:1418-1422.