Michael Walter

In this paper, we present a comprehensive computational framework aimed at suggesting genes whose transcriptional regulation is likely to be influenced by their chromosomal position. This framework provides a user-friendly web interface, enabling researchers to explore the positional properties of all human genes and their orthologs across species, with a focus on their relation to the telomeres. Our approach involves multiple scoring methods, each adjustable by users, representing different features of the genes' positional variation across species. The resulting rankings can be combined to identify candidate genes that may be subject to position effects. Furthermore, the ranking can be tailored to a specific set of reference genes. We evaluate the method within the context of TPE-OLD, a mechanism where telomeres can exert a direct influence on gene expression across considerable genomic distances, and empower researchers to delve deeper into genes of interest, analyzing their position across species and estimating their susceptibility to position effects like TPE-OLD. We also provide simple enrichment analyses of user-provided gene lists in relation to top-ranking candidate genes.

Telomeres are repetitive nucleotide sequences at the ends of each chromosome. It has been hypothesized that telomere attrition evolved as a tumor suppressor mechanism in large long-lived species. Long telomeres can silence genes millions of bases away through a looping mechanism called telomere position effect over long distances (TPE-OLD). The function of this silencing mechanism is unknown. We determined a set of 2322 genes with high positional conservation across replicatively aging species that includes known and candidate TPE-OLD genes that may mitigate potentially harmful effects of replicative aging. Notably, we identified PPP2R2C as a tumor suppressor gene, whose up-regulation by TPE-OLD in aged human fibroblasts leads to dephosphorylation of p70S6 kinase and mammalian target of rapamycin suppression. A mechanistic link between telomeres and a tumor suppressor mechanism supports the hypothesis that replicative aging fulfills a tumor suppressor function and motivates previously unknown antitumor and antiaging strategies.