Abstract
Highly flexible gene expression programs are required to allow cell growth in the presence of a wide variety of chemicals. We used genome-wide expression analyses coupled with chromatin immunoprecipitation experiments to study the regulatory relationships between two very similar yeast transcription factors involved in the control of the multidrug resistance phenomenon. Yrm1 (Yor172w) is a new zinc finger transcription factor, the overproduction of which decreases the level of transcription of the target genes of Yrr1, a zinc finger transcription factor controlling the expression of several membrane transporter-encoding genes. Surprisingly, the absence of YRR1 releases the transcriptional activity of Yrm1, which then up-regulates 23 genes, 14 of which are also direct target genes of Yrr1. Chromatin immunoprecipitation experiments confirmed that Yrm1 binds to the promoters of the up-regulated genes only in yeast strains from which YRR1 has been deleted. This sophisticated regulatory program can be associated with drug resistance phenotypes of the cell. The program-specific distribution of paired transcription factors throughout the genome may be a general mechanism by which similar transcription factors regulate overlapping gene expression programs in response to chemical stress.
Highlights
Cerevisisae contains a number of genes encoding transcriptional activators that exist as protein pairs (2)
Yrm1 Can Act as a Specific Inhibitor of Yrr1—We recently described the genome-wide regulatory properties of YRR1, a gene encoding a Zn2Cys6 zinc finger transcription factor (20)
We showed that 15 genes, mostly encoding plasma membrane proteins, are directly up-regulated by various mutated forms of Yrr1
Summary
MAT␣ his3⌬1 leu2⌬0 lys2⌬0 ura3⌬0 MAT␣ his3⌬1 leu2⌬0 lys2⌬0 ura3⌬0 YOR172W::kanMX4 MATa ura ade leu his trp289 MATa ura ade leu his trp289 YRR1::His6-URA3-His MAT␣ leu 112 ura his3-⌬200 trp1-⌬190 lys801 suc2-⌬9 MelϪ MAT␣ leu 112 ura his3-⌬200 trp1-⌬190 lys801 suc2-⌬9 MelϪ YRR1::3X HA-774. Genome-wide analyses have established that the sets of target genes directly regulated by these three transcription factors display considerable overlap (3, 4, 20). Most of these co-regulated genes encode for proteins involved in the structural organization of the plasma membrane. YOR172W, referred to here as YRM1 (for yeast reveromycin resistance modulator) is homologous (41% identities) to YRR1. The situation turned out to be more complex than expected: Yrm acts as a transcription factor and interacts with the promoter of the target genes only in the absence of Yrr. The sets of target genes directly regulated by YRR1 or YRM1 are similar, but not identical. Alternative promoter occupancy plays a key role in this cross-regulation adding a new degree of complexity to the cell drug response
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