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A growing body of research is revealing several processes that make DNA available for gene expression. In some cases, all eight histone proteins in a nucleosome are evicted from the DNA strand. In others, a pair of histones is removed, leaving six histone proteins in place. The histone pairs can be removed ahead of a polymerase and then repositioned behind it by molecules known as chaperones, creating a space for the polymerase to march past the histones.
In 1998, Danny Reinberg, an HHMI investigator at New York University, discovered a chaperone called FACT, for “facilitates chromatin transcription,” and in 2003 reported its function. FACT removes one specific histone pair, allowing an RNA polymerase to read the spooled DNA. “What you create is a way for the polymerase to invade the nucleosome and go through,” Reinberg explains.
Specific regions of DNA that control gene activity can also become nucleosome-free “in the blink of an eye,” says HHMI investigator Steven Henikoff at the Fred Hutchinson Cancer Research Center in Seattle. Highly specific DNA-binding proteins recruit enzymes that strong-arm the nucleosomes from their positions. In a January 2008 review in Nature Reviews Genetics, Henikoff described a combination of effects, including the work of histone chaperones, “remodeling” complexes, and other chemical modifications that determine how easily nucleosomes are destabilized. He is also investigating the unique conformation of nucleosomes at the constricted center of the chromosome, the centromere, and their implications for chromatin inheritance and centromere evolution.
There's still much to learn about the processes by which dislodging histones and nucleosomes or loosening DNA from its spool can direct which genes are turned on or off. Reinberg is specifically interested in how gene activation or silencing determines how a cell acquires its identity. For instance, in stem cells, which still have the potential to become a variety of cell types, “you find that the chromatin is more relaxed, more flexible, more uncommitted” than in cells with specific destinies such as liver cells, pancreatic cells, or neurons, Reinberg explains.
Likewise, “housekeeping genes,” which are always on because they are required for essential functions by nearly all cells, have very relaxed, open chromatin. However, unneeded genes—for example, genes in a pancreatic cell that are specific to liver function—are tightly packed and inaccessible to transcription machinery. Reinberg has reported that histones play a key role in directing chromatin to remain open and relaxed or to pack down tightly by means of chemical “tags” that attach to the histones.
Photo: Bizuayehu Tesfaye / AP, ©HHMI