Genome-Wide siRNA-Based Functional Genomics of Pigmentation Identifies Novel Genes and Pathways That Impact Melanogenesis in Human Cells

Link to original article

by Anand K. Ganesan, Hsiang Ho, Brian Bodemann, Sean Petersen, Jayavani Aruri, Shiney Koshy, Zachary Richardson, Lu Q. Le, Tatiana Krasieva, Michael G. Roth, Pat Farmer, Michael A. White

Author Summary

Aberrant pigment regulation correlates with skin disorders, opthalmologic disorders, and neurologic disorders. While extensive studies have identified regulators of mouse coat color, the regulation of human skin phenotypic variation is less well understood. To give a broader picture of the molecular regulators of melanogenesis in human cells, we used a genome-wide siRNA functional genomics approach to identify 92 novel regulators of melanin production in heavily pigmented MNT-1 melanoma cells.

Our screen identified several genes that converge to regulate tyrosinase, the rate-limiting step in pigment production, in both MNT-1 cells and primary melanocytes. Some of the identified genes were selectively active in different genetic backgrounds, suggesting that they may regulate human phenotypic variation. Small molecule inhibition of a family of novel pigment regulators was sufficient to impair pigment production in melanocytes.

Additionally, our screen identified molecular machinery known to support autophagosome biosynthesis as putative regulators of melanogenesis. In vitro co-localization studies and autophagy-deficient mice provided evidence that normal melanogenesis requires the same molecular machinery used by the autophagy pathway.

Taken together, these results illustrate the utility of genome wide siRNA screening approaches for identifying genes, novel pharmacologic agents, and pathways that regulate differentiated cellular phenotypes.

(Via PLoS Genetics: Archived Table of Contents.)