Tangled Up in Spools: Surprise change to chromosome protein silences genes (Chromatin; Silencing)
Authors: Davenport R. John 
Published: August 2003

Like a lot of people, DNA has trouble expressing itself when it's tightly wound. Chemical changes in protein spools around which DNA coils can tighten the spools, thereby shutting off genes. This silencing process also protects DNA, preventing it from breaking or swapping segments. Two studies identify a silencing-related chemical change in an unusual place: far from the end of a protein spool, where such changes usually appear. The finding will prod scientists to examine the entire spools when unraveling the complex signals that control silencing.

Stretched out, a human's DNA would span about 2 meters. But inside cells, DNA scrunches up around proteins called histones. Adding acetyl, methyl, or phosphate groups to histones alters how DNA winds around the proteins, exposing or shielding certain stretches. Yeast and worms with extra copies of a silencing protein called Sir2 reproduce longer than normal, suggesting that sheltering DNA slows aging (see
Kaeberlein Perspective
). Scientists had previously found modifications that affect silencing only in tails that protrude off the ends of histone proteins. Two groups have now uncovered an alteration on the protein's body.

In 1998, chromosome biologist Daniel Gottschling of the Fred Hutchinson Cancer Research Center in Seattle and colleagues identified a yeast protein called Dot1p that encourages silencing. Analysis of Dot1p's sequence suggested that it tacks methyl groups onto proteins. Now the researchers have probed whether Dot1p targets histones. They mixed yeast chromosomes with Dot1p and a radioactive methyl donor and found the methyl group in the middle of a histone protein called H3. In a separate study, molecular biologist Kevin Struhl and colleagues at Harvard Medical School in Boston diced yeast H3 and measured the mass of each piece to locate alterations. Like the first team, this group found an extra methyl group on a lysine positioned 79th in the amino acid chain and demonstrated that Dot1p put it there.

Each team then replaced H3's lysine 79 with an amino acid that can't accept a methyl group. Yeast cells with the mutant H3 showed reduced silencing in several regions of the genome, including the telomeres, which protect chromosome ends and might guard against cellular aging (see
"More Than a Sum of Our Cells"
). Further studies hint at possible mechanisms. In cells with mutant H3, Sir2 and a related protein bound to telomeres poorly. Struhl speculates that the H3 methyl group docks Sir proteins. Gottschling disagrees, positing that the methyl group instead deters binding of Sir proteins to inappropriate sites. In normal cells, about 10% of the genome carries unmethylated histones; Gottschling suggests that telomeres and other silenced sequences compose these areas and that Sir proteins concentrate there. In cells with mutant H3, Sir proteins disperse more widely through the genome than normal, which, Gottschling proposes, dilutes their ability to silence target regions.

Figuring out how histones help shush genes has always been complicated, even when scientists focused on the tails. Now, says biochemist David Allis of the University of Virginia in Charlottesville, "we have to think of the whole histone as fair game." Apparently it's too early to wrap up silencing into a tidy package.
--R. John Davenport; suggested by Nick Bishop

H. H. Ng, Q. Feng, H. Wang, H. Erdjument-Bromage, P. Tempst, Y. Zhang, K. Struhl, Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association.
Genes Dev.
16
, 1518-1527 (2002).
[Abstract/Full Text]
[Hyperlink should work by 21 June 2002.]

F. van Leeuwen, P. R. Gafken, D. E. Gottschling, Dot1p modulates silencing in yeast by methylation of the nucleosome core.
Cell
109
, 745-756 (2002).
[Abstract]
[Full Text]