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Human Pigmentation Genes Identified With Gene Editing Screen

NEW YORK – Findings from a genetic screen focused on human pigmentation contributors has uncovered a suite of new and known genes involved in boosting melanin production, including components of pathways involved in everything from transcriptional regulation and RNA processing to endosomal organelle transport.

"Our study reveals a plethora of melanin-promoting genes, with broad implications for human variation, cell biology, and medicine," first author Vivek Bajpai, a chemical and systems biology researcher affiliated with the University of Oklahoma and Stanford University School of Medicine, and his colleagues wrote in a study published in Science on Thursday.

Using a CRISPR-Cas9- and sequencing-based genetic screen, the investigators searched for genes affecting melanin accumulation in pigment-containing melanocyte cells based on side light scatter patterns measured by flow cytometry in human melanocytes or pigmented cell lines at different stages of maturation. These cells included human pluripotent stem cell-derived melanocytes and a cell line generated from melanoma.

"The more-pigmented cells scattered light more than less-pigmented cells, which was recorded as changes in [the] side-scatter parameter of flow cytometry," Bajpai said in an email. "Using side-scatter, we were able to separate the variably pigmented cells, which were then examined by next-generation sequencing to uncover the identity of deleted gene."

The melanin polymer is synthesized in specialized subcellular compartments known as melanosomes in melanocyte pigment cells, Bajpai explained. He noted that while humans carry a consistent number of pigment cells in their skin, variation in melanin levels leads to a range of skin colors across individuals and populations.

The team's genetic screening approach led to 169 melanosome biogenesis-related genes, including 135 genes not linked to human pigmentation in the past. Nearly 68 percent of the suspected melanin-related genes showed enhanced expression in melanocyte samples from individuals with darker pigmentation — results backed up by follow-up RNA sequencing analyses.

At least some genes identified in the current melanin screen coincided with skin color variation patterns found in human cell lines and mouse models, including genes that appear to have been subjected to local adaptation in different human populations.

In their follow-up functional analyses — including immunohistochemistry on skin samples from mice missing specific gene candidates — the investigators demonstrated that a gene called KLF6 codes for a transcription factor involved in the maturation of melanosomes, while pigmentation is dialed down in the absence of the gene.

Another gene — an endosomal trafficking complex component-coding gene called COMMD3 — appeared to influence pigmentation via endosomal transport-related changes in acidity in melanosomes. Those pH changes, in turn, can impact the activity of a tyrosinase enzyme involved in melanin production, Bajpai noted.

"[T]hese and other hits from our screen merit further exploration in the context of other diseases," he and his coauthors suggested, "because aberrant melanin production is associated not only with skin pigmentation disorders but also with Parkinson's disease and auditory disorders, which have been linked to loss of neuromelanin in substantia nigra and cochlear melanin in the inner ear, respectively."

More generally, Bajpai noted that the light scattering-based cell separation and CRISPR screening strategies used could be applied to other melanin producing species, including fungi and bacteria, particularly since microbes capable of melanin production tend to have enhanced abilities to infect humans or crop plants.

"By discovering and targeting such melanin producing genes, we can potentially create intervention against these microbial diseases," he said.