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These chemical tags, or modifications, are believed to orchestrate this gene-activation decision by telling an octamer when to jump off a DNA strand or by directing DNA to loosen from its histone spools. Such modifications include additions or subtractions of methyl, acetyl, and phosphate groups that bring additional instructions to the genetic code, telling the cell which genes should be active and which should be silent. “These histone modifications tell a cell, ‘hey, read me, I'm really important at this time,’” Luger says.
Rockefeller's Allis describes these chemical modifications with an analogy he borrows from former colleague Art Beaudet, of Baylor College of Medicine: If you were scanning a book's pages, underlines, italics, or bold type would help you find your words and sentences faster. So while letters in the alphabet often don't change (like bases in DNA), the words take on new meaning, more emphasis. In 1996, his lab isolated the first transcription-associated histone acetyltransferase, an enzyme that adds an acetyl group to certain amino acids. A month later, a research team led by HHMI investigator Stuart Schreiber at Harvard University reported the first deacetylase, which removes acetyl groups from histone proteins. Allis likens the process to writing and erasing. “Now almost all these marks are known to have a pairwise system of ‘on’ and ‘off’ enzymes.” Acetyl groups play a central role in gene expression by negating positive charge and opening up chromatin; their removal is thought by some to reverse this process. Researchers suspect that acetylation is somehow preparing the chromatin for transcription by altering contacts between histone tails and DNA in chromatin higher-order structures.
Histone tails are richly studded with modifications, but recent studies have also revealed that important chemical markers occur on histone bodies. Chemical markers on both the tails and histone bodies are believed to serve a host of functions, from attracting other cellular proteins to directing chromatin structure and determining which genes are active or silent. But the significance of their locations is not yet clear. “The functions of modifications in the tails versus in the body are still murky,” Luger says.
Many fundamental questions remain. “You have this incredibly long thread containing information in an incredibly confined space within a cell. Somehow the cell knows in this mess which genes to find at appropriate times,” Luger says. She compares it to the proverbial needle in a haystack, but instead of just finding the needle, you have to find many different-colored needles, “first red, then yellow, then green—and you have to find them within two seconds,” she explains. “How on earth does the cell do that? Not only does the cellular machinery know that it has to find these genes, but it also knows how. The mechanisms for this are truly awe-inspiring.”
Understanding these chemical signals in intimate detail is of pressing importance because a growing body of evidence suggests that histone modifications have close connections to disease, obesity, and other health effects. HHMI investigator Li-Huei Tsai at the Massachusetts Institute of Technology studies the cellular mechanisms underlying Alzheimer's disease. In the advanced stages of Alzheimer's, degeneration of neurons is accompanied by severe impairment of learning and memory. She and her colleagues created a mouse model that allowed them to test whether novel chemicals could restore learning in mice, even after a significant number of neurons have died.
Photo: Charles Peterson