Accelerated telomere shortening in the human inactive X chromosome

Telomeres are nucleoprotein complexes at the end of eukaryotic chromosomes, with important roles in the maintenance of genomic stability and in chromo some segregation. Normal somatic cells lose telomeric repeats with each cel l division both in vivo and in vitro. To address a potential role of nuclea r architecture and epigenetic factors in telomere-length dynamics, the leng th of the telomeres of the X chromosomes and the autosomes was measured in metaphases from blood lymphocytes of human females of various ages, by quan titative FISH with a peptide nucleic-acid telomeric probe in combination wi th an X-chromosome centromere-specific probe. The activation status of the X chromosomes was simultaneously visualized with antibodies against acetyla ted histone H4. We observed an accelerated shortening of telomeric repeats in the inactive X chromosome, which suggests that epigenetic factors modula te not only the length but also the rate of age-associated telomere shorten ing in human cells in vivo. This is the first evidence to show a differenti al rate of telomere shortening between and within homologous chromosomes in any species. Our results are also consistent with a causative role of telo mere shortening in the well-documented X-chromosome aneuploidy in aging hum ans.