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That view has changed. Today, these architectural proteins are recognized as essential to nearly every fundamental cellular process.
Their highly dynamic and confounding behavior, however, makes histones difficult to understand. Scientists are still trying to figure out how the bonds between DNA and histones affect gene expression and how a staggering array of chemical modifications to histones activates or silences specific genes. It appears that these modifications help determine cell fate and likely play important roles in health and disease.
Histones arrange the two meters of DNA found in every living human cell into a compact library that fits within the nucleus, just two micrometers in diameter. The histones somehow render the long, unwieldy threads of DNA into an organized message.
DNA and histones have opposite chemical charges, so they cling to each other. A length of DNA—about 150 base pairs—neatly wraps around a group of eight histone proteins (two copies each of H2A, H2B, H3, and H4) to form a nucleosome.
Nucleosomes line up like beads on the string of DNA. Each histone possesses a floppy tail that hangs from the body of the nucleosome. Between each nucleosome, 50 base pairs of “linker” DNA serve as the string between the beads, spacing the nucleosomes evenly. Thirty million nucleosomes are needed to package all the DNA in a human cell into the cell's chromatin, the structural material of chromosomes.
“If you don't have histones, your DNA will be much like a ball of yarn that your cat got into,” says Luger, a self-described “old timer” in histone research. “Histones make the packaging ordered so that the information isn't lost, and they prevent the tangles.” This is fundamentally important, says Luger. “If the cell gets knots in its DNA, it can't divide and it can't replicate itself.”
Since organisms first began storing their genetic material inside a true nucleus, histones have had a fundamental role in DNA packaging. The H4 histone protein is so highly conserved throughout evolution that only 2 of its 102 amino acids vary among organisms from pea plants to cows. At some point in evolutionary history, DNA simply became too long and unwieldy for the cell, says David Allis, a biochemist and chromatin expert at the Rockefeller University. “Seemingly, histones were the solution,” he says. “That packaging strategy must have just been so good it was well worth keeping.”
Photo: Joshua Lawton / AP, ©HHMI.