“Telomere position effect: regulation of gene expression with progressive telomeres shortening over long distances,”

REGULATORY ROLE: Early in life, when telomeres (red) are long, chromosome looping brings them into contact with particular genes (green) (1). As cells age, their telomeres shorten. Through mechanisms that are not yet understood, this alters chromosome looping and telomeres’ interactions with genes, leading to age-related changes in gene expression (2). Imaging using 3D-FISH (right panels) illustrates the distance between a certain gene and long (top) and short (bottom) telomeres.ILLUSTRATION © STEVE GRAEPEL; IMAGES COURTESY OF JERRY SHAY

EDITOR'S CHOICE IN GENETICS & GENOMICS

The paper
J.D. Robin et al., “Telomere position effect: regulation of gene expression with progressive telomeres shortening over long distances,” Genes Dev, 28:2464-76, 2014.

Telomeres are DNA repeats at the ends of chromosomes that protect genetic material from degradation. Because DNA polymerase cannot fully replicate the ends of chromosomes, telomeres shorten each time a cell divides. Telomeres also prevent the ends of chromosomes from fusing to one another by recruiting protective protein caps.

New work led by Jerry W. Shay and Woodring Wright of the University of Texas Southwestern Medical Center in Dallas demonstrates that telomeres are more than just buffer zones. The team found that as chromosomes fold within the nucleus, telomeres come into contact with faraway genes and alter their expression. As telomeres shorten, which happens with aging, chromosome looping and gene-expression patterns change.

“I’m delighted with this evidence that the [telomere] sequence may actually be doing some regulation and that the decrease of the sequence in some cells may drastically affect the way they are behaving,” says Mary-Lou Pardue, who studies telomeres at MIT and was not involved in the research. She points out that telomeres are longer and have a more complex sequence than should be necessary to simply protect the chromosome ends.

Previous work had shown that genes near telomeres are repressed. Shay says that he and his colleagues began to suspect that telomeres were regulating more than just nearby genes when they found that the expression of a gene called ISG15 increased as the telomeres of its chromosomes shortened, even while genes closer to the ends of the chromosomes remained unaffected.

Using a modified Hi-C technique, Shay and his colleagues mapped DNA looping in a 10-million-base-pair–long region of human chromosome 6. They found that, in cells with long telomeres, the telomeres interacted with multiple regions of the genome through intricate looping patterns. Imaging of specific genes using 3D-FISH revealed that, as the researchers manipulated telomere length, looping patterns reconfigured. Genes that had once been associated with telomeres were now relatively far away from them.

The researchers next used microarrays to analyze how telomere length affects gene expression across multiple chromosomes. They found that at least 144 genes within 10 million base pairs of a telomere sequence showed alterations in expression dependent on telomere length.

Finally, the researchers chose individual genes, including ISG15, whose expression is dependent on telomere length and assessed whether modifications in DNA folding accompany modifications in gene expression. Indeed, these genes’ expression changed in concert both with telomere shortening and with looping-related changes in their telomere proximity.

The molecular mechanisms by which telomeres modulate gene expression remain unclear, as do the evolutionary reasons for telomeres’ regulatory role. Shay speculates that telomere shortening can modulate gene expression so that it is appropriate for a cell’s life stage. When telomeres become too short, cell division arrests, for instance. This allows the body to limit the number of times cells divide and avoid cancerous growth. Shay suggests that cells could alter gene expression to slow cell division in ailing cells even before telomeres become critically shortened. Or telomere shortening could trigger gene expression in healthy cells at pivotal times during development, such as during puberty or menopause. “The possibilities are endless and potentially very important,” Shay says.