The eukaryotic genome can be up to 130 billion base pairs long, but required to fit inside each cell nucleus. To do this, DNA is tightly wrapped around histone proteins in bead-like clusters. Each cluster is called a nucleosome. For years, mapping experiments had revealed that nucleosomes favored particular DNA sequences, reflecting the ability of certain DNA sequences to bend more sharply and wrap around histones. Still, whether such preferences actually meant DNA coded for the positions of nucleosomes in vivo was unclear.
Then, in 2006, Eran Segal at the Weizmann Institute of Science, and Jonathan
Widom at Northwestern University, and their colleagues, revealed they could predict
nucleosome position based on DNA sequence alone with roughly 50%
accuracy—significantly better than the 35% predicted by
"It really brought together a number of disparate observations made in the past decade or two and synthesized them into a clear global model for how things might work," says Jason Lieb at the University of North Carolina. The model the Hot Paper proposed proved "provocative," he adds, and helped trigger a wave of new research.
Nucleosome mapping efforts have been revolutionized several times over in the
space of just two years thanks to breakthroughs in DNA sequencing technology, Widom
says. High-resolution tiling microarray studies have yielded millions of
measurements of where nucleosomes tend to appear across the
Such advances in mapping nucleosomes lead to improvements in predicting
nucleosome position based on DNA sequence,
A number of experiments inspired by the 2006 paper are now underway to test how well DNA sequences code for nucleosome positions, Lieb says. "The problem with an in vivo study of nucleosome positioning, like you had with Segal and his colleagues' paper, is that there are all these transcription binding factors and enzymes there in the nucleus that could move nucleosomes around, so it's hard to separate out the influence that DNA sequences play," he explains. "The next round of experiments will take an in vitro approach using actual genomic DNA to see where nucleosomes like to bind in the absence of any other factors." Widom notes his group and others are hard at work on such experiments, although no one has published any results yet.
Not everyone is convinced DNA sequences play a huge role in nucleosome
position. Results from Frank Pugh's lab at Pennsylvania State University suggest
that nucleosome positioning "just has to do with packing," says
The bigger picture
Will nucleosome findings in yeast hold true for other organisms, including
humans? Recent nucleosome mapping experiments in Caenorhabditis elegans
conducted by Andrew Fire at Stanford University suggest that sequence-directed
nucleosome positioning may play a less prominent role in multicellular
The biggest remaining question might be what role the nucleosome code has played in evolution. "DNA has evolved not just to code the information that will go on to be translated into proteins [or] read by regulatory proteins, but on top of all that, it has to code how it should be packaged. So what kind of constraint has this placed on way DNA can change over time in eukaryotes?" Lieb asks.
To explore the nucleosome code's impact on evolution researchers are
exploring how well nucleosome positioning sequences are preserved within and between
species. For instance, Naama Barkai at the Weizmann Institute of Science and her
colleagues found last year that DNA rigidity is conserved across yeast species at
"It will be very interesting to see how genomes evolved to deal with the constraints that nucleosomes can impose," Widom says.