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  • The EMBO Journal (2004) 23, 2281 - 2292
  • doi:10.1038/sj.emboj.7600233

Published online: 13 May 2004

The unfolded protein response represses differentiation through the RPD3-SIN3 histone deacetylase

Martin Schröder1, Robert Clark2, Chuan Yin Liu1,a and Randal J Kaufman1,2

  1. Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, USA
  2. Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI, USA

Correspondence to:

Randal J Kaufman, Department of Biological Chemistry, Howard Hughes Medical Institute, HHMI, University of Michigan Medical Center, 4570 MSRB II, 1150 W Medical Center Dr., Ann Arbor, MI 48109-0650, USA. Tel.: +1 734 763 9037; Fax: +1 734 763 9323; E-mail: kaufmanr@umich.edu

aPresent address: Cell Biology-ICND 216, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA

Received 23 October 2003; Accepted 19 April 2004

In Saccharomyces cerevisiae, splicing of HAC1 mRNA is initiated in response to the accumulation of unfolded proteins in the endoplasmic reticulum by the transmembrane kinase-endoribonuclease Ire1p. Spliced Hac1p (Hac1ip) is a negative regulator of differentiation responses to nitrogen starvation, pseudohyphal growth, and meiosis. Here we show that the RPD3-SIN3 histone deacetylase complex (HDAC), its catalytic activity, recruitment of the HDAC to the promoters of early meiotic genes (EMGs) by Ume6p, and the Ume6p DNA-binding site URS1 in the promoters of EMGs are required for nitrogen-mediated negative regulation of EMGs and meiosis by Hac1ip. Co-immunoprecipitation experiments demonstrated that Hac1ip can interact with the HDAC in vivo. Systematic analysis of double deletion strains revealed that HAC1 is a peripheral component of the HDAC. In summary, nitrogen-induced synthesis of Hac1ip and association of Hac1ip with the HDAC are physiological events in the regulation of EMGs by nutrients. These data also define for the first time a gene class that is under negative control by the UPR, and provide the framework for a novel mechanism through which bZIP proteins repress transcription.

  • Keywords:

    • differentiation,
    • meiosis,
    • nitrogen sensing,
    • nutritional control of gene regulation,
    • unfolded protein response