Abstract
Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal.
Highlights
All mammalian telomeres are composed of large tracts of repeated 5’-TTAGGG sequences
We recently described a phenomenon in which genes near chromosome ends are regulated by telomere length-dependent loops
We show that the expression of the hTERT gene itself is regulated by telomere position effect—over long distances (TPE-OLD)
Summary
All mammalian telomeres (the ends of linear chromosomes) are composed of large tracts of repeated 5’-TTAGGG sequences. Telomeres are maintained by many essential genes, including the six-component shelterin (TRF1, TRF2, POT1, TIN2, RAP1, and TPP1) and the CST (CTC1-STN1-TEN1) complexes [1,2]. Impairment of these genes is closely associated with age-related clinical pathology and defects in germ cell and stem cell maintenance [3,4,5]. Human embryonic stem cells and transit amplifying adult progenitor stem-like cells express hTERT and have active/functional telomerase that can fully or partially maintain telomeres during the substantial number of cell divisions required in fetal development [7]. Tight regulation of telomerase and progressive telomere shortening are thought to be an initial barrier to the early onset of cancer
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