An early question about aging skin led to answers on how cells code for their location.

Howard Chang found that one long intervening noncoding RNA, called HOTAIR, is important in breast cancer. Too much of it encourages a primary breast cancer to spread.

Early in his research career, Howard Chang asked a simple question: what happens to skin cells as an organism ages? Using genetic technologies just emerging in 2000, Chang explored his question and revealed another complexity of skin—one that he's still puzzling over.

Chang's curiosity also led him into a new realm of study: long noncoding RNAs. In the past year, the HHMI early career scientist at Stanford University debuted a technique for determining RNA structures, and now he's making novel links between a specific type of RNA and human health.

Chang is a dermatologist with M.D. and Ph.D. degrees. During his clinical residency in dermatology, he worked in the Stanford research lab of HHMI investigator Patrick O. Brown, where he learned about microarrays. Chang saw the technology as an opportunity to determine the genetic differences between young and old skin cells.

		There’s An App for RNA See screenshots from Howard Chang’s iPhone app that lets the user navigate RNA structures.

He collected skin samples from banks of foreskin tissue taken from newborn boys. From adults, he gathered biopsies of arm, scalp, and back skin. It was widely assumed that skin was skin—identical all over the body. Chang's research revealed, on the contrary, that differences in gene activity among the tissues stemmed not only from age but also location.

"I realized these cells have functional differences based on where they are," says Chang. "It's like a built-in address code."

Chang started frequenting the morgue, collecting skin samples from different body parts of cadavers. Using microarrays, he discovered that the differences in gene activity among skin cells could be traced to Hox genes, a large family of genes already known to control positioning of body parts during development.

In 2004, Chang started his own lab. His team devised a method to look at expression of the 39 Hox genes—whether each is turned on or off—and also at expression of the DNA flanking each gene.

In humans, more than 200 of these surrounding regions were actively expressed. The researchers found this puzzling, since these regions of DNA are transcribed into RNA but never go on to produce proteins. They're called noncoding RNAs. His lab began to focus on one called HOTAIR. The researchers hypothesized that blocking cells from making HOTAIR would affect the neighboring Hox gene. But instead, the expression of a Hox gene on a completely different chromosome changed.

"This raised the idea that these RNAs can have very profound effects all over the genome," says Chang. His lab is beginning to understand these far-reaching effects.

Photo: Ramin Rahimian

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