Abstract
The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.
Highlights
Human cutaneous pigmentation is dependent on melanin pigment production by epidermal and follicular melanocytes.Melanin synthesis is controlled by the melanocortin receptor type 1 (MC1R) which encodes a 7-pass transmembrane G-protein-coupled receptor
We analysed the gene signature associated with red hair color (RHC) co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants
By PPI network analysis, we identified two gene co-expression networks that reached statistically significant values in loss-offunction MC1R variants cutaneous cells
Summary
Human cutaneous pigmentation is dependent on melanin pigment production (eumelanin and pheomelanin) by epidermal and follicular melanocytes.Melanin synthesis is controlled by the melanocortin receptor type 1 (MC1R) which encodes a 7-pass transmembrane G-protein-coupled receptor. In wild-type MC1R melanocytes, activation of the receptor by the α-melanocyte stimulating hormone (α-MSH) promotes www.impactjournals.com/oncotarget the synthesis of eumelanin pigment (dark pigment), reduces UV-induced oxidative stress and enhances DNA repair through base-excision repair and NER mechanisms which repairs UV-photoproducts [1]. Mitra D et al observed that the absence of pheomelanin is protective against melanoma development in mice models [7] They detected high levels of oxidative DNA and lipid damage in RHC mice in a UV-independent model which still leads to oxidative damage. We h[2]ave previously reported that co-cultured melanocytes and keratinocytes harbouring loss-of-function MC1R variants show a constitutive overexpression of genes involved in oxidative phosphorylation pathway and DNA repair mechanisms [8]
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