Inherited long telomeres induce a genome-wide transcriptional response in budding yeast

Abstract

Eukaryotes typically maintain telomere length within a defined range. While short telomeres are known to activate DNA damage responses and limit cell proliferation, long telomeres are associated with extended proliferative capacity. The broader cellular consequences of long telomeres are comparatively less well understood. In budding yeast Saccharomyces cerevisiae, long telomeres have been shown to influence gene expression at specific loci, but whether long telomeres affect transcription genome-wide has not been reported. Here, we analysed transcriptomes in a lineage that inherited long telomeres (originally due to a rif2{Delta} mutation). Transcriptomes were assessed over two rounds of mitosis and meiosis in the absence of the rif2{Delta} mutation. We show that strains with long telomeres exhibit a distinct gene expression profile, including upregulation of membrane transporters and downregulation of a smaller subset of genes. Both up- and down-regulated genes were distributed across the genome, arguing against a purely telomere-proximal effect on gene expression. Affected genes were enriched for Rap1 binding sites, consistent with a model in which long telomeres sequester telomere-associated transcriptional regulators, such as Rap1, and thereby affect gene expression at non-telomeric binding sites for these regulators. Accordingly, the magnitude of transcriptional changes was greatest in strains with the longest telomeres. Together, our findings demonstrate that long telomeres induce a genome-wide transcriptional response that can accompany inherited long telomeres across generations. Similar effects of long telomeres are likely to occur in other eukaryotes, including humans, where long telomeres are associated with disease. Article summaryTelomeres protect chromosome ends, and their length is tightly regulated. While short telomeres are known to be harmful, the effects of long telomeres are less well understood. Using budding yeast, we show that inherited long telomeres alter the expression of dozens of genes across the genome, particularly membrane transporters. These changes are consistent with a model in which long telomeres sequester regulatory proteins away from other loci. Our findings may have broader implications in more complex organisms, including humans.