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Molecular and Cellular Biology, July 2001, p. 4347-4368, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4347-4368.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Transcriptional Profiling Shows that Gcn4p Is a Master Regulator of Gene Expression during Amino Acid Starvation in Yeast

Krishnamurthy Natarajan,1,dagger Michael R. Meyer,2 Belinda M. Jackson,1 David Slade,2 Christopher Roberts,2 Alan G. Hinnebusch,1,* and Matthew J. Marton2,*

Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, Bethesda, Maryland 20892,1 and Rosetta Inpharmatics, Kirkland, Washington 980342

Received 8 February 2001/Returned for modification 16 March 2001/Accepted 3 April 2001

Starvation for amino acids induces Gcn4p, a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. In an effort to identify all genes regulated by Gcn4p during amino acid starvation, we performed cDNA microarray analysis. Data from 21 pairs of hybridization experiments using two different strains derived from S288c revealed that more than 1,000 genes were induced, and a similar number were repressed, by a factor of 2 or more in response to histidine starvation imposed by 3-aminotriazole (3AT). Profiling of a gcn4Delta strain and a constitutively induced mutant showed that Gcn4p is required for the full induction by 3AT of at least 539 genes, termed Gcn4p targets. Genes in every amino acid biosynthetic pathway except cysteine and genes encoding amino acid precursors, vitamin biosynthetic enzymes, peroxisomal components, mitochondrial carrier proteins, and autophagy proteins were all identified as Gcn4p targets. Unexpectedly, genes involved in amino acid biosynthesis represent only a quarter of the Gcn4p target genes. Gcn4p also activates genes involved in glycogen homeostasis, and mutant analysis showed that Gcn4p suppresses glycogen levels in amino acid-starved cells. Numerous genes encoding protein kinases and transcription factors were identified as targets, suggesting that Gcn4p is a master regulator of gene expression. Interestingly, expression profiles for 3AT and the alkylating agent methyl methanesulfonate (MMS) overlapped extensively, and MMS induced GCN4 translation. Thus, the broad transcriptional response evoked by Gcn4p is produced by diverse stress conditions. Finally, profiling of a gcn4Delta mutant uncovered an alternative induction pathway operating at many Gcn4p target genes in histidine-starved cells.

* Corresponding author. Mailing address for Alan G. Hinnebusch: Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, Bldg. A, Rm. B1A13, Bethesda, MD 20892. Phone: (301) 496-4480. Fax: (301) 496-6828. E-mail: ahinnebusch{at}nih.gov. Mailing address for Matthew J. Marton: Rosetta Inpharmatics, Kirkland, WA 98034. Phone: (425) 636-6563. Fax: (425) 636-6501. E-mail: mmarton{at}rii.com.

dagger Present address: School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.

Molecular and Cellular Biology, July 2001, p. 4347-4368, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4347-4368.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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