Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA.

Robyn M. Perrin, Natalie D. Fedorova, Woo Bok Jin, Robert A. Cramer, Jennifer R. Wortman, Heenam Kim, William C. Nierman, Nancy P. Keller

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

Secondary metabolites, including toxins and melanins, have been implicated as virulence attributes in invasive aspergillosis. Although not definitively proved, this supposition is supported by the decreased virulence of an Aspergillus fumigatus strain, DeltalaeA, that is crippled in the production of numerous secondary metabolites. However, loss of a single LaeA-regulated toxin, gliotoxin, did not recapitulate the hypovirulent DeltalaeA pathotype, thus implicating other toxins whose production is governed by LaeA. Toward this end, a whole-genome comparison of the transcriptional profile of wild-type, DeltalaeA, and complemented control strains showed that genes in 13 of 22 secondary metabolite gene clusters, including several A. fumigatus-specific mycotoxin clusters, were expressed at significantly lower levels in the DeltalaeA mutant. LaeA influences the expression of at least 9.5% of the genome (943 of 9,626 genes in A. fumigatus) but positively controls expression of 20% to 40% of major classes of secondary metabolite biosynthesis genes such as nonribosomal peptide synthetases (NRPSs), polyketide synthases, and P450 monooxygenases. Tight regulation of NRPS-encoding genes was highlighted by quantitative real-time reverse-transcription PCR analysis. In addition, expression of a putative siderophore biosynthesis NRPS (NRPS2/sidE) was greatly reduced in the DeltalaeA mutant in comparison to controls under inducing iron-deficient conditions. Comparative genomic analysis showed that A. fumigatus secondary metabolite gene clusters constitute evolutionarily diverse regions that may be important for niche adaptation and virulence attributes. Our findings suggest that LaeA is a novel target for comprehensive modification of chemical diversity and pathogenicity.

Original languageEnglish
JournalPLoS Pathogens
Volume3
Issue number4
DOIs
Publication statusPublished - 2007 Apr 1

Fingerprint

Aspergillus fumigatus
Peptide Synthases
Virulence
Multigene Family
Genes
Gliotoxin
Genome
Polyketide Synthases
Siderophores
Aspergillosis
Mycotoxins
Melanins
Mixed Function Oxygenases
Reverse Transcription
Iron
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Immunology
  • Microbiology
  • Parasitology
  • Virology

Cite this

Perrin, R. M., Fedorova, N. D., Jin, W. B., Cramer, R. A., Wortman, J. R., Kim, H., ... Keller, N. P. (2007). Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathogens, 3(4). https://doi.org/10.1371/journal.ppat.0030050

Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. / Perrin, Robyn M.; Fedorova, Natalie D.; Jin, Woo Bok; Cramer, Robert A.; Wortman, Jennifer R.; Kim, Heenam; Nierman, William C.; Keller, Nancy P.

In: PLoS Pathogens, Vol. 3, No. 4, 01.04.2007.

Research output: Contribution to journalArticle

Perrin, RM, Fedorova, ND, Jin, WB, Cramer, RA, Wortman, JR, Kim, H, Nierman, WC & Keller, NP 2007, 'Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA.', PLoS Pathogens, vol. 3, no. 4. https://doi.org/10.1371/journal.ppat.0030050
Perrin, Robyn M. ; Fedorova, Natalie D. ; Jin, Woo Bok ; Cramer, Robert A. ; Wortman, Jennifer R. ; Kim, Heenam ; Nierman, William C. ; Keller, Nancy P. / Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. In: PLoS Pathogens. 2007 ; Vol. 3, No. 4.
@article{1438c178e54b4492a494274bd043fdcb,
title = "Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA.",
abstract = "Secondary metabolites, including toxins and melanins, have been implicated as virulence attributes in invasive aspergillosis. Although not definitively proved, this supposition is supported by the decreased virulence of an Aspergillus fumigatus strain, DeltalaeA, that is crippled in the production of numerous secondary metabolites. However, loss of a single LaeA-regulated toxin, gliotoxin, did not recapitulate the hypovirulent DeltalaeA pathotype, thus implicating other toxins whose production is governed by LaeA. Toward this end, a whole-genome comparison of the transcriptional profile of wild-type, DeltalaeA, and complemented control strains showed that genes in 13 of 22 secondary metabolite gene clusters, including several A. fumigatus-specific mycotoxin clusters, were expressed at significantly lower levels in the DeltalaeA mutant. LaeA influences the expression of at least 9.5{\%} of the genome (943 of 9,626 genes in A. fumigatus) but positively controls expression of 20{\%} to 40{\%} of major classes of secondary metabolite biosynthesis genes such as nonribosomal peptide synthetases (NRPSs), polyketide synthases, and P450 monooxygenases. Tight regulation of NRPS-encoding genes was highlighted by quantitative real-time reverse-transcription PCR analysis. In addition, expression of a putative siderophore biosynthesis NRPS (NRPS2/sidE) was greatly reduced in the DeltalaeA mutant in comparison to controls under inducing iron-deficient conditions. Comparative genomic analysis showed that A. fumigatus secondary metabolite gene clusters constitute evolutionarily diverse regions that may be important for niche adaptation and virulence attributes. Our findings suggest that LaeA is a novel target for comprehensive modification of chemical diversity and pathogenicity.",
author = "Perrin, {Robyn M.} and Fedorova, {Natalie D.} and Jin, {Woo Bok} and Cramer, {Robert A.} and Wortman, {Jennifer R.} and Heenam Kim and Nierman, {William C.} and Keller, {Nancy P.}",
year = "2007",
month = "4",
day = "1",
doi = "10.1371/journal.ppat.0030050",
language = "English",
volume = "3",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA.

AU - Perrin, Robyn M.

AU - Fedorova, Natalie D.

AU - Jin, Woo Bok

AU - Cramer, Robert A.

AU - Wortman, Jennifer R.

AU - Kim, Heenam

AU - Nierman, William C.

AU - Keller, Nancy P.

PY - 2007/4/1

Y1 - 2007/4/1

N2 - Secondary metabolites, including toxins and melanins, have been implicated as virulence attributes in invasive aspergillosis. Although not definitively proved, this supposition is supported by the decreased virulence of an Aspergillus fumigatus strain, DeltalaeA, that is crippled in the production of numerous secondary metabolites. However, loss of a single LaeA-regulated toxin, gliotoxin, did not recapitulate the hypovirulent DeltalaeA pathotype, thus implicating other toxins whose production is governed by LaeA. Toward this end, a whole-genome comparison of the transcriptional profile of wild-type, DeltalaeA, and complemented control strains showed that genes in 13 of 22 secondary metabolite gene clusters, including several A. fumigatus-specific mycotoxin clusters, were expressed at significantly lower levels in the DeltalaeA mutant. LaeA influences the expression of at least 9.5% of the genome (943 of 9,626 genes in A. fumigatus) but positively controls expression of 20% to 40% of major classes of secondary metabolite biosynthesis genes such as nonribosomal peptide synthetases (NRPSs), polyketide synthases, and P450 monooxygenases. Tight regulation of NRPS-encoding genes was highlighted by quantitative real-time reverse-transcription PCR analysis. In addition, expression of a putative siderophore biosynthesis NRPS (NRPS2/sidE) was greatly reduced in the DeltalaeA mutant in comparison to controls under inducing iron-deficient conditions. Comparative genomic analysis showed that A. fumigatus secondary metabolite gene clusters constitute evolutionarily diverse regions that may be important for niche adaptation and virulence attributes. Our findings suggest that LaeA is a novel target for comprehensive modification of chemical diversity and pathogenicity.

AB - Secondary metabolites, including toxins and melanins, have been implicated as virulence attributes in invasive aspergillosis. Although not definitively proved, this supposition is supported by the decreased virulence of an Aspergillus fumigatus strain, DeltalaeA, that is crippled in the production of numerous secondary metabolites. However, loss of a single LaeA-regulated toxin, gliotoxin, did not recapitulate the hypovirulent DeltalaeA pathotype, thus implicating other toxins whose production is governed by LaeA. Toward this end, a whole-genome comparison of the transcriptional profile of wild-type, DeltalaeA, and complemented control strains showed that genes in 13 of 22 secondary metabolite gene clusters, including several A. fumigatus-specific mycotoxin clusters, were expressed at significantly lower levels in the DeltalaeA mutant. LaeA influences the expression of at least 9.5% of the genome (943 of 9,626 genes in A. fumigatus) but positively controls expression of 20% to 40% of major classes of secondary metabolite biosynthesis genes such as nonribosomal peptide synthetases (NRPSs), polyketide synthases, and P450 monooxygenases. Tight regulation of NRPS-encoding genes was highlighted by quantitative real-time reverse-transcription PCR analysis. In addition, expression of a putative siderophore biosynthesis NRPS (NRPS2/sidE) was greatly reduced in the DeltalaeA mutant in comparison to controls under inducing iron-deficient conditions. Comparative genomic analysis showed that A. fumigatus secondary metabolite gene clusters constitute evolutionarily diverse regions that may be important for niche adaptation and virulence attributes. Our findings suggest that LaeA is a novel target for comprehensive modification of chemical diversity and pathogenicity.

UR - http://www.scopus.com/inward/record.url?scp=34250371692&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34250371692&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.0030050

DO - 10.1371/journal.ppat.0030050

M3 - Article

VL - 3

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 4

ER -