Molecular Medicine Israel

Telomeres Affect Gene Expression

As telomeres shorten with age, genes as far as 1,000 kilobases away could be affected, including one responsible for an inherited muscle disease

DUX4, a gene responsible for the genetic disease facioscapulohumeral muscular dystrophy (FSHD), is normally silenced because it sits next to a telomere—a protective DNA sequence that caps the ends of chromosomes, according to a study published today (May 5) in Nature Structural and Molecular Biology. But as telomeres shorten, as they do with age, DUX4 expression climbs, which may explain the late onset of FSHD. Another gene, called FRG2, which sits 100 kilobases away from the telomere, is also affected by telomere length.

“This was completely unexpected,” said coauthor Guido Stadler at the University of Texas Southwestern Medical Center in Dallas, since earlier studies showed that telomeres only silence genes a few kilobases away. Stradler and his colleagues even found preliminary evidence that telomeres can also influence a gene even more distant on the chromosome, 1,000 kilobases away—an effect that disappears as the telomere shortens.

“We think that DUX4 and FRG2 are the tip of an iceberg,” he said: due to shrinking telomeres, many genes might gradually become more active as we get older, which may be important for several diseases of old age. “This represents a very significant general advance in our understanding of how telomere shortening may affect human biology.”

FSHD is an inherited disease that causes the upper body muscles to gradually waste away. Most such genetic disorders manifest during early childhood, but FSHD is unusual in symptoms usually appear when people are in their teens or early 20s….

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