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Growth-regulated recruitment of the essential yeast ribosomal protein gene activator Ifh1


Regulation of ribosome biogenesis is central to the control of cell growth1. In rapidly growing yeast cells, ribosomal protein (RP) genes account for approximately one-half of all polymerase II transcription-initiation events1, yet these genes are markedly and coordinately downregulated in response to a number of environmental stress conditions2,3,4, or during the transition from fermentation to respiration5. Although several conserved signalling pathways (TOR, RAS/protein kinase A and protein kinase C) impinge upon RP gene transcription1, little is known about how initiation at these genes is controlled. Rap1 (refs 6, 7) and more recently Fhl1 (ref. 8) were shown to bind upstream of many RP genes. Here we show that the essential protein Ifh1 binds to and activates many RP gene promoters under optimal growth conditions in Saccharomyces cerevisiae. Ifh1 is recruited to RP gene promoters through the forkhead-associated domain of Fhl1. Ifh1 binding decreases when RP genes are downregulated either by TOR inhibition or nutrient depletion, and is restored after release from starvation or upon regulated induction of IFH1 expression. These findings indicate a central role for Ifh1 and Fhl1 in RP gene regulation.

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Figure 1: Ifh1, Fhl1 and Rap1 binding at RP gene (RPG) promoters, and mRNA levels during logarithmic growth, before the diauxic shift or after TOR inhibition.
Figure 2: Rapamycin-sensitive recruitment of Ifh1 to an ectopic site (GAL7) via the FHA domain of GBD–Fhl1 hybrids.
Figure 3: Ifh1 directly activates RP gene transcription.


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We thank J. Warner, E. Di Mauro, K. Mizuta, G. Ammerer, P. Thuriaux and M. Tyers for discussions; J. Warner, K. Struhl and M. Tyers for communicating unpublished results; A. Bianchi for comments on the manuscript; members of the Shore laboratory for discussions; P. Descombes, C. Barraclough, C. Delucinge, O. Schaad, P. Soularue and X. Gidrol for help with microarray experiments and analysis; S. Gasser for providing antibodies; and N. Roggli for artwork. This work was supported by the Human Frontier Science Program, the Swiss National Science Foundation, the NCCR program ‘Frontiers in Genetics’ (Swiss National Science Foundation), and the Canton of Geneva.

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Correspondence to David Shore.

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Supplementary information

Supplementary Methods (DOC 66 kb)

Supplementary Table 1

Fhl1-myc and Ifh1-myc binding to intergenic regions in cells untreated, or treated for 90 min with rapamycin. For each experiment, we generated a list of enriched intergenic regions (according to the criteria described in Supplementary Information, Methods) that was sorted according to p-value. For each enriched locus, we indicated the intergenic region identifier, the median log enrichment ratio, the p-value, the ORF(s) under the control of this promoter region on both strands (if applicable) and the Gene Ontology (GO; if applicable) of individual genes except RP genes. (HTM 233 kb)

Supplementary Figure 1

a, Ifh1-myc, Fhl1-myc, and Rap1 protein levels during diauxic shift, rapamycin treatment and re-growth from stationary phase. b, Ifh1-myc binding at RP gene promoters is restored immediately after release from starvation (see Supplementary Information, Methods). (PDF 229 kb)

Supplementary Figure 2

Genome-wide binding of Fhl1-myc and Ifh1-myc to intergenic regions and global (genome-wide) association of Fhl1-myc and Ifh1-myc with RP gene promoters, as measured in the absence of rapamycin and 90 min following rapamycin treatment. (PDF 215 kb)

Supplementary Figure 3

Ifh1 directly activates RP gene transcription. This Figure is a reproduction of Fig. 3a in which individual gene names can be read. (PDF 199 kb)

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Schawalder, S., Kabani, M., Howald, I. et al. Growth-regulated recruitment of the essential yeast ribosomal protein gene activator Ifh1. Nature 432, 1058–1061 (2004).

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