Chromosome Biology: Short Telomeres Can't Reach
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RESEARCH HIGHLIGHTS CHROMOSOME BIOLOGY Short telomeres can’t reach It has long been known that telo lengths. Upon TERT clearance the reintroduction of TERT into meres can silence the expression from the cells, telomere shortening subclones with short telomeres, and long, but of nearby genes — a phenomenon resumes, and the following experi consequently the lengthening of not short, known as the telomere position ments were performed before this their telomeres, reversed the expres effect (TPE) — and that telomere could lead to replicative senescence sion pattern of these genes. Thus, telomeres shortening can affect TPE, albeit by or DNA damage signalling. Using telomere length-dependent, long- are involved unknown mechanisms. A team led subclones with long and short range chromosome interactions may in forming by Shay and Wright had previously telomeres, the authors performed enhance or repress gene expression, a chromosome found an example in human cells of Hi-C (chromosome conformation phenomenon termed TPE over long a gene (ISG15) located 1 Mb away capture (3C) followed by high- distances (TPE-OLD). loops from the end of chromosome 1, the throughput sequencing) modified The authors then examined expression of which increased as to produce a high-resolution map of telomere-dependent looping in telomeres shortened even though the chromosomal interactions along TPE-OLD using 3D-FISH with the expression of genes closer to the the short arm of chromosome 6 probes for several TPE-OLD genes telomere remained unchanged. They (6p), which was chosen because, located on chromosome 1p. They now report that long, but not short, endogenously, its telomeres are very observed substantial differences in telomeres are involved in forming short. The interaction of the 6p tel the localization of the loci in cells chromosome loops of up to 10 Mb, omeres with two genes (the farthest with long or short telomeres, with and can affect high-order chromatin being 7.5 Mb away) were validated the genes being adjacent to the 1p structure and gene expression. and quantified by 3C and by three- subtelomeric region in cells with The enzyme telomerase reverse dimensional fluorescence in situ long telomeres, but separated from it transcriptase (TERT), which is hybridization (3D-FISH), and this in cells with short telomeres. Thus, responsible for maintaining telomere revealed that as telomeres shorten, the changes in telomere length- length, is not expressed in most adult telomere-dependent chromosome dependent gene expression are cells. By expressing it ectopically for looping is diminished. accompanied by changes in the high- varying durations in human primary Next, the authors analysed gene order organization of the chromatin. myoblasts and fibroblasts, the authors expression in myoblasts with long How telomere–chromatin loops established a collection of isogenic (15 kb) and short (6 kb) telomeres are formed in human cells awaits subclones with uniform clonal, but using microarrays, and found that further investigation. As the extent differential interclonal, telomere the expression of genes located up and nature of TPE-OLD was found to 10 Mb from telomeres of various to vary between chromosomes, chromosomes changed when the genes and cell types, it is likely that telomeres shortened. The differential additional mechanisms are respon expression of 14 genes (the majority sible for establishing gene- and of which showed increased expres cell‑specific effects. sion) in different subclones of fibro Eytan Zlotorynski blasts and myoblasts was validated ORIGINAL RESEARCH PAPER Robin, J. D. et al. by droplet digital PCR (ddPCR), a Telomere position effect: regulation of gene technique for quantifying nucleic expression with progressive telomere shortening 3D-FISH of the subtelomeric region of human chromosome 1p (red) and the ISG15 acids that gives an absolute number over long distances. Genes Dev. locus (green) in cells with long telomeres (left) and short telomeres (right). http://dx.doi.org/10.1101/gad.251041.114 (2014) Images courtesy of J. Shay, University of Texas Southwestern Medical Center, USA. of molecules per input. Importantly, NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 15 | DECEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved.