Every skin cell is not the same, and Howard Chang wants to know why. For example, how is it that skin on the scalp generates long hairs, but skin on the bottom of the foot doesn't? Like other cells in the body, skin cells are brimming with location-specific gene activity, according to Chang. These genes act as a global positioning system to help the cells know where they should be and how they should act. He has found that the regulators of these genes have a broader impact than anticipated. Errors in these complex gene programs can lead to birth defects and cancer metastasis.
Chang, a practicing dermatologist and researcher at the Stanford University School of Medicine, has discovered that molecules called long noncoding RNAs allow cells to situate themselves in the body and behave properly. As their name implies, noncoding RNAs don't serve as templates for protein production. Instead, they bind to other RNAs and to proteins to stimulate or repress gene activity, so that, for example, those skin cells on your head or eyebrows grow hair and cells on your nose do not.
To uncover the molecular details about long noncoding RNAs, Chang is developing new bioinformatics and genomics tools and methodologies. He is trying to define their structure, their interactions with genes and chromosomes, and their function in living tissue. He's focusing on long noncoding RNAs he has identified that are synthesized from four chromosomal regions—termed the HOX gene loci—that control the three-dimensional form of a developing embryo.
The HOX loci encompass dozens of genes and possibly hundreds of long noncoding RNAs that must be turned on at precise locations and times during development to tell the embryo exactly what body part to make. Discovering how noncoding RNAs work should shed light on how cells learn and remember where they are located in the body and on general rules of how large groups of genes are coordinated for complex tasks.
Chang first became interested in long noncoding RNAs after he discovered one in 2007 that bound to enzymes that modify chromatin, the protein-DNA complex that makes up chromosomes. Up to that time, a small number of long noncoding RNAs had been studied, and they were thought to affect only the behavior of genes in their immediate neighborhood. Chang found the first example of a long noncoding RNA that can control chromatin on a completely different chromosome. Distance was not a barrier. "The finding implied long noncoding RNAs are capable of acting on possibly hundreds of targets in the genome," Chang says. "We are now trying to find out how."
Chang is comfortable in uncharted territory. As a teenager, he moved with his family from Taiwan to the United States. He learned English by watching television and by joining the high school debate team. After working in laboratories throughout high school and experiencing the joy of discovery, Chang followed in his father's footsteps by becoming a physician, but he also obtained a Ph.D., with Nobel laureate David Baltimore at the Massachusetts Institute of Technology.
During his clinical training in dermatology, Chang worked in the lab of HHMI investigator Patrick Brown, a pioneer in microarray technology at Stanford University. It was there that Chang discovered that fibroblasts, connective tissue cells that support the skin's structure, express different HOX genes depending on their anatomic location on the body. Researchers had previously thought HOX genes were only active embryonically, but while in Brown's lab, Chang showed that HOX genes are expressed in adult fibroblasts. Fibroblasts, says Chang, are "the bearers of positional memory in tissues and organs."
The gene expression pattern in shoulder fibroblast cells from two different individuals is more similar than the gene expression pattern in fibroblasts from the shoulder and from the thigh in the same individual, Chang says. As an independent scientist he found that long noncoding RNAs are involved in those location-based differences in gene expression, and now his group is studying how they do it.
Chang says that learning more about long noncoding RNAs may improve understanding of how large sets of genes are turned on or off together—critical processes in development, aging, and cancer. He has begun to find clues to gene regulation in aging, indicating that it may not just be a matter of wear and tear on the body; there may be ways to slow it down. "I am quite optimistic that understanding how large groups of genes work together—creating patterns, shapes, and programs—will lead to breakthroughs in biology and medicine."