The Histone Code

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For years, histone proteins have had a relatively boring reputation as proteins that just help coil several feet of the really interesting molecule, DNA, into a tiny ball small enough to fit into a chromosome.

But lately, the tail ends of the mostly globular histones are gaining more attention as regulators of the genes inside the DNA. Modifications, such as acetyl groups, to the histone tails, have been known for years to correlate with gene expression. Acetylated histones seem to mark genes that are on and actively being transcribed into RNA.

Originally it was thought that the addition of acetyl groups loosened the DNA wrapped around bundles of histones, called nucleosomes, by disrupting electrical interactions between the proteins and the genetic material. And, indeed, DNA must be uncoiled or loosened before a gene can be transcribed.

But because acetyl groups are on very specific amino acids, usually lysines, many scientists believe the acetyls form a code on the histones that controls whether the gene is turned on or off. Understanding the code and how it's printed onto the histones could lead to therapies that could shut down or turn on genes in diseases, like cancer, that have aberrant patterns of gene expression. Already, several drugs that prevent removal of acetyls are in Phase I or II trials.

Now, for the first time, the histone code that controls the expression of a gene has been fully deciphered by Dr. Dimitris Thanos, associate professor of biochemistry and molecular biophysics, and his postdoctoral researcher, Dr. Theodora Agalioti. The research was published in the Nov. 1 issue of Cell.

The code the two deciphered controls the expression of the human interferon-beta gene. Interferon-beta is an anti-viral protein that is produced after a human cell encounters a virus. Before the gene is transcribed, some amino acids in the tails of two histones, H3 and H4, near the beginning of the interferon beta gene are acetylated.

Drs. Thanos and Agalioti found that the placement of acetyls in vivo is not random and, therefore, has the potential to encode information. After infecting human cells with a virus and then identifying which histone amino acids were acetylated, the researchers found that the same three lysines in the tails were acetylated every time the cells were infected. Two lysines on the H3 histone were acetylated, along with one lysine on the H4 histone.

The two researchers then deciphered what the code meant by disrupting individual acetylation events. The results show the H4 acetyl group is needed for the recruitment of a large protein complex that loosens the DNA from the histones. The two H3 acetyls are needed for the recruitment of a second complex that pushes the core of histones away from the beginning of the interferon gene so transcription can proceed.

To show that the precise placement of acetyl groups, and not the electrical patches they produce, is important to the recruitment of the complexes, the researchers made nucleosomes that possessed only acetylated H3 or acetylated H4 tails. The altered nucleosomes produced similar electrical areas as the normal nucleosome but could not recruit both of the protein complexes.

So far, only the histone code of the interferon gene has been deciphered to this level of detail, Dr. Thanos says. The next step, he says, is to look at other genes to see if they use the same code. Already, there are hints that a gene, INO1, in yeast may use the same code, since the same lysines are acetylated in the yeast and interferon genes. Dr. Thanos says not all genes need a histone code to begin transcription. "If the nucleosome is not in an important area of the gene, the histone code is not so important," Dr. Thanos says.

Another outstanding question is what controls the printing of the code onto histones. Because the enzymes that print the code are brought to the histones by a group of transcription factors, the enhanceosome, Drs. Thanos and Agalioti believe the shape of enhanceosome may control which parts of the histone are acetylated. The enhanceosome, in turn, is controlled by the regulatory DNA sequences it binds, so the information in the histone code is really an extension of information in the DNA, Dr. Thanos says.

"The dream is to look at the regulatory DNA and read the histone code," Dr. Thanos says.

The National Institutes of Health and the March of Dimes supported this research.