Sci. Aging Knowl. Environ., 21 December 2005
Loose Chromosomes Sink Cells
Gene-silencing mechanism falters in patients with premature aging disorder
"Just relax" might be good advice for stressed-out holiday travelers, but it could be disastrous for chromosomes, according to work presented at the American Society for Cell Biology meeting in San Francisco, California, on 13 December. The study suggests that chromosomes uncoil somewhat in patients with a disease that resembles premature aging, an alteration that could unleash genes whose products aren't needed.
Children with the fatal genetic disease Hutchinson-Gilford progeria syndrome (HGPS) seem to grow old before their time. They lose their hair, their skin thins, their bones grow brittle, and their arteries clog (see "Of Hyperaging and Methuselah Genes"). Most afflicted individuals die in their teens from a stroke or heart attack. In 2003, researchers fingered the genetic flaw that triggers HGPS: a mutation in the gene for lamin A (see "Lamin-tation"). The protein weaves a mesh that supports the cell's nucleus, and it's also necessary for copying DNA and making messenger RNA. A 2004 study by cell biologist Robert Goldman of Northwestern University's Feinberg School of Medicine in Chicago, Illinois, and colleagues suggested a connection between HGPS and gene control. Cells mothball stretches of DNA that they are not currently using. They accomplish the feat by coiling the strands tightly in a structure called heterochromatin. Goldman's work hinted that heterochromatin vanishes from HGPS cells. The researchers sought to confirm its disappearance and determine whether mutant lamin A was involved.
Heterochromatin condenses when DNA wraps tightly around the proteins called histones. Cinching up the chromosomes requires that a specific amino acid in one type of histone acquires methyl groups. To track heterochromatin, the scientists reared skin cells from a girl with HGPS and added an antibody that grabs the methyl-carrying amino acid. Using cells from females makes it easy to detect compacted DNA, Goldman notes, because they harbor one inactive X chromosome in each cell that is "a mass of heterochromatin." After duplicating for several generations, cells from the HGPS patient had shed their methyl groups, but cells from her healthy sister retained the molecular adornment. Normal cells engineered to pump out the faulty form of lamin A dropped their methyl marks, too. HGPS cells pump out less of the messenger RNA that codes for the methyl-adding enzyme, the researchers showed, which could explain the loss of methylated histones. Heterochromatin usually bears a coating of RNA. Although this layer didn't vanish in the HGPS cells, it showed signs of fraying. That finding suggests that although the chromosomes in the HGPS cells didn't unravel, they had started to loosen up. Overall, the work indicates that faulty lamin A meddles with histone methylation, Goldman says.
The work deserves praise for homing in on a change that might trigger HGPS defects, says cell biologist Susan Michaelis of Johns Hopkins University in Baltimore, Maryland. Now, the trick is to tease out which of the alterations researchers have identified cause the symptoms of HGPS, she says. For example, Goldman's group also found that faulty lamin A remains stuck to the nuclear membrane during cell division; in contrast, the normal protein disperses. Cell biologist Harald Herrmann of the German Cancer Research Center in Heidelberg describes the study as "a real breakthrough" because it shows that the protein can tamper with chromosome organization. Next, researchers need to establish that faulty lamin A activates silenced genes, he says. Further work might reveal whether uptight chromosomes keep cells healthy.
December 21, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150