Competitive Promoter Occupancy by Two Yeast Paralogous Transcription Factors Controlling the Multidrug Resistance Phenomenon

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. 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. Promoter occupancy by transcription factors is a critical step in establishment of the developmental program. In several cases, the transcription factor binds all its potential target genes, and signaling events at specific promoters are responsible for determining which genes are expressed. Alternatively, the regulation of target gene selection could occur at the level of DNA binding. New tools have opened up new opportunities for studying the program-specific distribution of transcription factors (1Zeitlinger J. Simon I. Harbison C.T. Hannett N.M. Volkert T.L. Fink G.R. Young R.A. Cell. 2003; 113: 395-404Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar), revealing a high level of sophistication in the DNA binding program. Paralogous transcription factors often seem to interact with similar promoters, although little is known about the specific mechanism involved. Gene duplication, by conferring new evolutionary possibilities, provides an important source of diversity in the regulatory processes controlling gene expression. This is particularly true of the genes encoding transcription factors. The genome of the yeast Saccharomyces cerevisisae contains a number of genes encoding transcriptional activators that exist as protein pairs (2Goffeau A. Barrell B.G. Bussey H. Davis R.W. Dujon B. Feldmann H. Galibert F. Hoheisel J. Jacq C. Johnston M. Louis E.J. Mewes