DCA has also received a fair amount of attention in the lay press

s that have previously been identified in other cell or animal PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19862565 models as modifiers of neuronal a-synuclein toxicity, such as sir-2.1 and genes involved in vesicle trafficking. Based on these findings, we expect other genes from our screen to provide insight into neuronal a-synuclein pathology as well. Future studies in neurons will resolve which of these gene processes are implicated in neuronal a-synuclein pathology. In a screen performed previously for modifiers of polyglutamine aggregation in C. elegans, we found a large variety of proteasomal genes and chaperones. These genes are typically found to be involved in protein misfolding and aggregation and are suggested to be generally involved in protein-misfolding diseases. Surprisingly, very few of such genes were found in the a- synuclein screen. Genetic mapping studies have identified a limited set of genes responsible for skin and eye color variability. Pigment production involves the concerted actions of transcriptional, translational, and intracellular trafficking machinery. MITF, the master regulator of melanogenesis in the mouse hair follicle, activates the transcription of tyrosinase, the rate limiting step in melanogenesis. Tyrosinase is translated in the endoplasmic reticulum and is glycosylated in the Golgi apparatus. Tyrosinase activity is restricted to the melanosome, a melanin specific organelle of poorly defined origin. While the subtle variation in human skin color is thought to be the result of the complex interaction of multiple genes, the majority of mouse mutants described have segmental or complete absence of pigment. Recent studies have identified partial loss of function mutations that impact the shade of melanin in zebrafish and human skin, but the spectrum of gene targets that regulate pigment shade is unknown. Melanin is expressed in different end organs conferring different functions. Melanin protects the skin, eyes, and brain from toxic insults. Melanin in the inner ear impacts sound conduction. Loss of melanin is thought to siRNA-Based Functional SB 1317 web Genomics of Pigmentation 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 agen