New research done by University of Texas Southwestern Medical Center’s Jerry W. Shay and Woodring Wright shows that telomeres act as more than just buffers and alter gene expression.
“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.” – The Scientist