April 6, 2009

Volume 87, Number 14

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Behind The Scenes

Orchestrating Genetic Expression

Epigenetic modifications alter chromatin landscape, turn genes on and off

Ivan Amato

Without changing a single genetic letter in a multi-billion-letter genome, chemical modifications of chromatin, the macromolecular stage inside a cell's nucleus that bears DNA and that constitutes chromosomes, play genes like notes in a life-long score. For the most part, that score is inherited at conception, but it also can be edited in two primary ways during gestation, early childhood, and perhaps throughout life, and can even be passed down to the next generation.

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BEYOND GENES Chromatin, the macromolecular stuff of chromosomes, undergoes two major types of epigenetic modifications—on the DNA and on the histone proteins of the nucleosomes central to the packing of DNA into a chromosome. These changes, which do not affect the sequence of nucleotides as genetic mutations do, have pivotal roles in gene expression, in development, in sickness, and in health.

One of these ways is DNA methylation. The placement of the archetypically simple four-atom methyl groups along a chromosome's DNA can, for example, shut down a tumor-suppressor gene, thereby depriving the body of proteins that normally keep cells from becoming cancerous. Or it can shut down the vast stretches of relic viral DNA in the human genome, a very good thing without which humanity probably wouldn't exist at all. A stretch of DNA with lots of methyl groups is effectively zipped closed; a stretch that has a dearth of methyl groups typically is open for business. Because some genes control the actions of many others, epigenetics methylation patterns "can have a huge influence on phenotype," epigenetics researcher Moshe Szyf of McGill University says.

Vidaza, a drug prescribed to patients with severe blood disorders and one of only four epigenetics-based drugs now in clinical use, is a demethylating agent. Presumably among its actions in patients' blood cells is the removal of methyl groups from tumor-suppressor genes that had been unduly methylated, shut down, and thereby unable to do their cancer-suppressing work.

The other major type of epigenetic modification occurs on the amino acids in the dangling tails of histone proteins, octets of which form into spools around which DNA winds like a fishing line. Whereas lots of DNA methylation in a particular stretch of DNA functions like a closed zipper on the chromosome, histone modifications either activate or silence their associated stretches of DNA by tightening or loosening the histone-DNA contacts and interspool packings; the looser situations are more welcoming of the transcription machinery that begins the DNA-to-protein translation.

Vorinostat, one of the four Food & Drug Administration-approved epigenetics-based drugs and also prescribed for certain cancers, works by inhibiting histone deacetylase (HDAC) enzymes that remove acetyl groups from histone tails. Such deacetylated histone proteins bear less positive charge and thereby are less effective at drawing in the negatively charged DNA that is nearby. The result is looser chromatin, more accessible DNA, and more gene expression.

Scientists have been uncovering a growing complexity to histone modification. Specific amino acids of specific histones get methylated, demethylated, acetylated, and deactylated, as well as phosphorylated, ubiquinated, and sumoylated, and that's not nearly the end of it. What's more, both DNA methylation and histone modifications recruit or repel other players to the chromatin stage, among them transcription factors and polymerases that promote genetic expression and short stretches of RNA that lock the DNA down or interfere with messenger RNA before it can get its protein-producing message outside of the nucleus. Trying to picture all of these processes operating in concert is like trying to watch everything going on in every nook and cranny of a large city at once. But that is exactly what the epigenetics research community aims to do.

Chemical & Engineering News

ISSN 0009-2347

Copyright © 2009 American Chemical Society