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Published On June 13, 2017

BASIC RESEARCH

Untangling Chromatin

More than marvels of biological architecture, structures within the cell nucleus may be intertwined with aging itself.

Chromatin, hardly a household word outside the realm of medical research, has remarkable properties. Composed of tightly bundled DNA, RNA and other proteins, chromatin is tucked into the nucleus of every human cell. And while that nucleus is a mere five microns or so in diameter—that’s five millionths of a meter—if the chromatin inside it were pulled straight, it would be about six and a half feet long.

Until recently, though, chromatin’s shape in the nucleus wasn’t considered especially important in itself. “People thought it was just a structural thing,” says Raul Mostoslavsky, a molecular biologist at the Mass General Cancer Center. Yet as technological advances allowed researchers to observe chromatin at ever-finer scales, that understanding was overturned.

Chromatin is not only fantastically compact but in constant motion. It opens and closes paths into its dense structure, so that genetic-instruction-carrying molecules can find their targets, and changes shape to arrange genes into new configurations. Chromatin dynamics have proved crucial to such fundamental cellular processes as cell division, DNA repair and protein production. “We now know chromatin is involved in almost every biological process,” says Mostoslavsky—including the processes of aging.

The foremost target of Mostoslavsky’s research is a gene called SIRT6. It belongs to a family of genes, the sirtuins, that are central to metabolism and DNA repair. Among its other roles, SIRT6 plays a large part in cell division and, as Mostoslavsky has found, the maturation of embryonic stem cells into their adult forms. Key to these functions is its role as a sort of chromatin control panel—a chromatin “factor,” in research argot—regulating those openings, closings and shape-changings. Mutations to SIRT6 have especially powerful effects. “It’s not just regulating one pathway,” Mostoslavsky says. “It regulates many characteristics.”

Mostoslavsky is particularly interested in how cancer exploits those gene variants. He has found that in colon cancer cells, SIRT6 mutations help turn glucose into energy, while pancreatic cancer cells tweak SIRT6 to activate a gene that limits cell growth. That a single gene could fuel cancer’s runaway proliferation in such different ways underscores the importance of SIRT6 and other chromatin factors.

During the past several years, mutations to genes affecting chromatin pathways have been linked to a host of cancers. Chromatin malfunctions have also been implicated in diabetes, heart disease, and neurodegenerative conditions such as Alzheimer’s disease. All these are considered age-related diseases, the risk of developing them increasing with age.

Aging is now understood to be a matter of senescence, the gradual deterioration of the body’s ability to heal itself. While much remains to be learned about the details of the processes involved in that decline, it now looks as though chromatin, so important to so many cellular functions, plays a key role.

“Just as we lose the capacity to run because our muscles are less fit, our cells become less fit in maintaining our genome,” Mostoslavsky says. “Some of the chromatin factors end up being expressed at the wrong levels. You get dysregulation.” Therapies that could be based on that insight are still in very early stages, he says—it's not easy to manipulate processes that have so many downstream consequences—but finding ways to address problems with chromatin might eventually help to extend human lives. Inevitably, the marvelously packed threads of the human genome start to unravel—but someday, perhaps, scientists will learn how to wrap them up again.