Telomere position effect in human cells
Telomeres are tracts of repetitive DNA that cap the ends of linear chromosomes. Each time
the chromosome is duplicated, a small amount of telomeric DNA is lost from the end due to
factors inherent in the mechanism of DNA replication. The result is a net shortening of
telomeres with each cell division, unless new repeats are synthesized through the action of
the enzyme telomerase. Most human somatic cells lack telomerase activity and so continued
cell division leads to telomere shortening. After a limited number of divisions (the “Hayflick
limit”), it is believed that a few critically shortened telomeres trigger a state of growth arrest
termed replicative senescence.
Genes near telomeres in yeast and other lower organisms have been shown to be
reversibly repressed, resulting in a variegated (mosaic) phenotype. This silencing has been
termed telomere position effect, or TPE. Because human telomeres shorten during cell
division, a similar effect in human cells could potentially be regulated by the age of the cell.
In the present work, telomere position effect was demonstrated in human cells by
comparing the expression of a luciferase reporter integrated either next to a telomere or at an
internal site. Despite the expected high variability within each group, a ten-fold decrease in
average luciferase activity was shown for the telomeric clones. Silencing was relieved by
treatment with a histone deacetylase inhibitor or BrdU, indicting that reduced expression was
not due to alterations in the gene itself. Elongation of telomeres by telomerase resulted in a
two to ten-fold increase in silencing specifically in telomeric clones. When a fluorescent
reporter was used, TPE in human cells produced a variegated phenotype, and spontaneous
reactivation of the transgene could be detected in non-expressing subclones. A screen of
candidate proteins identified hRap1 as a potential mediator of this effect. No effect of
telomere length was detected on the expression of several endogenous subtelomeric genes.
However, few candidates are currently available since knowledge concerning the detailed
structure of most chromosome ends is limited at present. A more detailed analysis of
subtelomeric gene expression will be an important future step since relief of silencing in
these regions has the potential to play an important role in human aging.