Endogenous genes regulated by telomere length

Reporter genes inserted immediately adjacent to telomeres are frequently repressed in cells of model organisms as well as human cells, a phenomena referred to as telomere position effect (TPE). TPE has been proposed to be involved in regulation of cellular senescence, cancer and aging. However, the identification of endogenous genes in human cells regulated by natural telomeres has not been reported. Here we show that the expression of interferon simulated gene 15 (ISG15, located on 1p36.33, G1P2) varies with telomere length. ISG15 expression (RNA and protein) increases in human cells with short telomeres, and decreases with the elongation of telomeres by human telomerase reverse transcriptase (hTERT). The up-regulation of ISG15 is independent of p53 and type I interferon, and is not due to replicative senescence and DNA damage. In human skin specimens obtained from various aged individuals, ISG15 was up-regulated in a subset of cells in older individuals. Our results demonstrate that endogenous human genes can be regulated by the length of telomeres prior to the onset of DNA damage signals, and it suggests that telomeres may be involved in the regulation of human physiology that contributes to the process of aging. Keywords: cell type comparison To identify endogenous genes regulated by telomere length, we prepared a microarray chip that we call the “telo-array”. The telo-array contains 1,323 subtelomeric genes (within 1,000kb from telomere) representing all 92 telomere ends. In addition, the telo-array has 92 random control genes, 12 housekeeping genes and 198 other genes. Total RNA isolated from human skin fibroblasts (BJ), lung fibroblasts (IMR90) and mammary epithelial cells (HME31) (Table 1) with different telomere lengths were hybridized to the telo-array, and the data were analyzed with GeneSpring software