A recent study led by an Indian-origin researcher has identified 135 new genes associated with the light-absorbing pigment known as melanin. An article recently published in the journal Science features research from Vivek Bajpai, PhD, lead author and an assistant professor in the School of Sustainable Chemical, Biological and Materials Engineering at the University of Oklahoma, and collaborators from Stanford University.
“Using CRISPR, we systematically removed more than 20,000 genes from hundreds of millions of melanocytes and observed the impact on melanin production”, said Bajpai.
To identify which genes influence melanin production, cells that lost melanin during the gene removal process needed to be separated from millions of other cells that did not. Using in vitro cell cultures, Bajpai developed a novel method to achieve this goal that detects and quantifies the melanin-producing activity of melanocytes. By passing light through the melanocytes, he could record if the light was either absorbed or scattered by the melanin inside.
“If there are a lot of melanin-producing melanosomes, the light will scatter much more than in cells with little melanin,” Bajpai said. “Using a process called side-scatter of flow cytometry, we were able to separate cells with more or less melanin, these separated cells were then analyzed to determine the identity of melanin-modifying genes. We identified both new and previously known genes that play important roles in regulating melanin production in humans,” he said.
The researchers found 169 functionally diverse genes that impacted melanin production. Of those, 135 were not previously associated with pigmentation. They further identified the function of two newly discovered genes: KLF6 and COMMD3. The DNA-binding protein KLF6 led to a loss of melanin production in humans and animals, confirming the role KLF6 plays in melanin production in other species as well. The COMMD3 protein regulated melanin synthesis by controlling the acidity of melanosomes.
Historically, darker pigmentation has been needed to protect against ultraviolet radiation in areas closer to the equator and for people who spend hours in direct sunlight. As humans moved into areas with less direct sunlight or fewer hours of daylight overall, less melanin was needed. Over time, this resulted in melanosomes that produced less melanin, thus absorbing more sunlight.
“By understanding what regulates melanin, we can help protect lighter-skinned people from melanoma, or skin cancer,” Bajpai said. “By targeting these new melanin genes, we could also develop melanin-modifying drugs for vitiligo and other pigmentation diseases.”
According to a release, the technological processes developed and used by the research team could also be applied to identify genes that regulate melanin production in fungi and bacteria. Melanin production in fungi and bacteria enables them to be more pathogenic to humans or crops. Researchers could develop effective interventions against these microbes and their diseases by discovering and targeting such melanin-producing genes.
A grant from the Oklahoma Center for Adult Stem Cell Research supported the study. Additional funding was provided by the U.S. Department of Defense, CA160997; Howard Hughes Medical Institute; National Institute of General Medical Sciences, NIH R35 GM131757; Stinehart-Reed Award; and the Ludwig Center for Cancer Stem Cell Research and Medicine.