Gis1 and Rph1 Regulate Glycerol and Acetate Metabolism in Glucose Depleted Yeast Cells

Abstract

Aging in organisms as diverse as yeast, nematodes, and mammals is delayed by caloric restriction, an effect mediated by the nutrient sensing TOR, RAS/cAMP, and AKT/Sch9 pathways. The transcription factor Gis1 functions downstream of these pathways in extending the lifespan of nutrient restricted yeast cells, but the mechanisms involved are still poorly understood. We have used gene expression microarrays to study the targets of Gis1 and the related protein Rph1 in different growth phases. Our results show that Gis1 and Rph1 act both as repressors and activators, on overlapping sets of genes as well as on distinct targets. Interestingly, both the activities and the target specificities of Gis1 and Rph1 depend on the growth phase. Thus, both proteins are associated with repression during exponential growth, targeting genes with STRE or PDS motifs in their promoters. After the diauxic shift, both become involved in activation, with Gis1 acting primarily on genes with PDS motifs, and Rph1 on genes with STRE motifs. Significantly, Gis1 and Rph1 control a number of genes involved in acetate and glycerol formation, metabolites that have been implicated in aging. Furthermore, several genes involved in acetyl-CoA metabolism are downregulated by Gis1.

Genome-wide expression analyses of the stationary phase model of ageing in yeast

“…MAPK and Ras/PKA pathway. Our results are in accordance with previous findings, particularly in calorie restriction (CR) studies (Orzechowski Westholm et al, 2012;Wei et al, 2008;Wei et al, 2009).…”

“…The Sp1-transcription factor (Gis1p orthologue) was found to be responsive to cellular redox state in mammals (Wei et al, 2008). Additionally, Gis1p and Rph1p regulate genes in acetate and glycerol metabolism (Orzechowski Westholm et al, 2012).…”

A Sequence-Specific Interaction between the Saccharomyces cerevisiae rRNA Gene Repeats and a Locus Encoding an RNA Polymerase I Subunit Affects Ribosomal DNA Stability

“…3). This upregulation is consistent with the known roles of these proteins in the regulation of RNAP II transcription (37,40,41). In contrast, the 20-copy rDNA strain showed a significant reduction in RPA135 transcript levels (P Ͻ 0.05, two-tailed, Student t test) (Fig.…”

Epigenetic Mechanisms of Longevity and Aging

“…The Gis1 related protein Rph1, which is also a H3K36 demethylase, affects yeast replicative lifespan (Sen et al, 2015) and has a role in gene expression in the stationary phase (Orzechowski Westholm et al, 2012). Surprisingly, deletion of GIS1 shortens lifespan, and this phenotype may result from activation of Acs2 (nuclear acetyl-CoA synthetase), promoting histone acetylation, while deletion of RPH1 extends lifespan via a mitochondria-to-nucleus signaling via gene repression at subtelomeres (Orzechowski Westholm et al, 2012; Schroeder et al, 2013).…”

“…Surprisingly, deletion of GIS1 shortens lifespan, and this phenotype may result from activation of Acs2 (nuclear acetyl-CoA synthetase), promoting histone acetylation, while deletion of RPH1 extends lifespan via a mitochondria-to-nucleus signaling via gene repression at subtelomeres (Orzechowski Westholm et al, 2012; Schroeder et al, 2013). All of the mutants mentioned in this section have markedly different gene expression profiles compared to wild type yeast, strongly indicative of large-scale epigenetic changes, although the exact changes driving longevity are undetermined.…”