Genome-wide transcriptome analysis of human epidermal melanocytes

Haltaufderhyde, Kirk; Oancea, Elena

doi:10.1016/j.ygeno.2014.09.010

Cited by 37 publications

(42 citation statements)

References 64 publications

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“…The identity of the putative GPCR that mediates the UVA phototransduction cascade remains unknown, but members of the retinal-dependent, light-sensitive opsin family are ideal candidates. Coincidentally, in HEMs, we and others have found expression of mRNA corresponding to several opsins [16][17][18][19][20]; opsin3 (OPN3), which has unknown physiological function, has significantly higher mRNA expression than any other detected opsin [18].…”

Section: Introductionmentioning

confidence: 97%

The human non-visual opsin OPN3 regulates pigmentation of epidermal melanocytes through interaction with MC1R

Özdeşlik

Olinski

Trieu³

et al. 2019

Preprint

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Opsins form a family of light-activated, retinal-dependent G-protein coupled receptors (GPCRs) that serve a multitude of visual and non-visual functions. Opsin3 (OPN3 or encephalopsin), initially identified in the brain, remains one of the few members of the mammalian opsin family with unknown function and ambiguous light-absorption properties. We recently discovered that OPN3 is highly expressed in human epidermal melanocytes-the skin cells that produce melanin. The melanin pigment is a critical defense against ultraviolet radiation and its production is mediated by the Gs-coupled melanocortin-1 receptor (MC1R). The physiological function and light-sensitivity of OPN3 in melanocytes is yet to be determined.Here we show that in human epidermal melanocytes OPN3 acts as a negative regulator of melanin production by interacting with MC1R and modulating its cAMP signaling. OPN3 negatively regulates the cAMP response evoked by MC1R via activation of the Gαi subunit of G-proteins, thus decreasing cellular melanin levels. In addition to their functional relationship, OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures and form a physical complex. Remarkably, OPN3 can bind retinal, but does not mediate light-induced signaling in melanocytes. Our results identify a novel function for OPN3 in the regulation of the melanogenic pathway in epidermal melanocytes. Our results reveal a light-independent function for the poorly characterized OPN3 and a novel pathway that greatly expands our understanding of melanocyte and skin physiology. Key words:Opsin3 | Encephalopsin | Melanocortin 1 Receptor | Pigmentation | Human Epidermal Melanocyte SignificanceOur data reveals a novel function for the non-visual opsin OPN3 in regulating the pigmentation of human melanocytes by interacting with and modulating the activity of MC1R.

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Section: Introductionmentioning

confidence: 97%

The human non-visual opsin OPN3 regulates pigmentation of epidermal melanocytes through interaction with MC1R

Özdeşlik

Olinski

Trieu³

et al. 2019

Preprint

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“…The identity of the putative G protein-coupled receptor (GPCR) that mediates the UVA phototransduction cascade remains unknown, but members of the retinal-dependent, light-sensitive opsin family are ideal candidates. Coincidentally, in HEMs, we and others have found expression of messenger RNA (mRNA) corresponding to several opsins (16)(17)(18)(19)(20): Among these, opsin 3 (OPN3), which has an unknown physiological function, has significantly higher mRNA expression than any other detected opsin (18).…”

mentioning

confidence: 94%

Human nonvisual opsin 3 regulates pigmentation of epidermal melanocytes through functional interaction with melanocortin 1 receptor

Özdeşlik

Olinski

Trieu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Opsins form a family of light-activated, retinal-dependent, G protein-coupled receptors (GPCRs) that serve a multitude of visual and nonvisual functions. Opsin 3 (OPN3 or encephalopsin), initially identified in the brain, remains one of the few members of the mammalian opsin family with unknown function and ambiguous light absorption properties. We recently discovered that OPN3 is highly expressed in human epidermal melanocytes (HEMs)-the skin cells that produce melanin. The melanin pigment is a critical defense against ultraviolet radiation (UVR), and its production is mediated by the Gαs-coupled melanocortin 1 receptor (MC1R). The physiological function and light sensitivity of OPN3 in melanocytes are yet to be determined. Here, we show that in HEMs, OPN3 acts as a negative regulator of melanin production by modulating the signaling of MC1R. OPN3 negatively regulates the cyclic adenosine monophosphate (cAMP) response evoked by MC1R via activation of the Gαi subunit of G proteins, thus decreasing cellular melanin levels. In addition to their functional relationship, OPN3 and MC1R colocalize at both the plasma membrane and in intracellular structures, and can form a physical complex. Remarkably, OPN3 can bind retinal, but does not mediate light-induced signaling in melanocytes. Our results identify a function for OPN3 in the regulation of the melanogenic pathway in epidermal melanocytes; we have revealed a light-independent function for the poorly characterized OPN3 and a pathway that greatly expands our understanding of melanocyte and skin physiology. opsin3 | encephalopsin | melanocytes | melanocortin 1 receptor | pigmentation U nlike most mammals, which have melanin-producing melanocytes predominantly in the hair follicle bulb (1), humans are uniquely equipped with melanocytes in the outermost layer of the skin, the epidermis (2, 3). These neural crest-derived melanocytes are the only source of the photoprotective pigment melanin in human skin, and thus are critical for the defense against solar ultraviolet radiation (UVR)-induced genotoxic damage (4-6).Solar UVR at the surface of the earth is composed of ∼5% short-wavelength UVB rays and ∼95% long-wavelength UVA rays. Much of our current knowledge about melanogenesis in epidermal melanocytes stems from the well-characterized UVBinduced melanin pathway (7). UVB elicits DNA damage in epidermal keratinocytes, triggering facultative skin darkening through increased melanin production in neighboring melanocytes (8). UVB-irradiated keratinocytes and melanocytes locally secrete α-melanocyte stimulating hormone (α-MSH), an agonist of the Gαs-coupled melanocortin 1 receptor (MC1R) that is primarily expressed on melanocytes (8,9). MC1R has a pivotal role in determining pigmentation, as several naturally occurring loss-offunction MC1R variants are associated with the redhead phenotype (10, 11) characterized by a pale complexion and increased sensitivity to UVR (12). Downstream, α-MSH-induced MC1R activation leads to stimulation of adenylyl cyclase (AC) and production of...

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“…These genes showed a pattern of up-regulation due to hybridization and also further up-regulation effected by UVB exposure. Among these 18 genes, 4 genes are related to melanin synthesis ( mitfa , tyr , tyrp1a , dct ), 3 genes are related to melanosome transport ( rab27 , rab38a , pmela ), 4 genes are related to pigmentation ( slc2a11b , slc24a5 , oca2, pax3b ), and 4 genes are melanoma/melanocyte marker ( tspan10 , slc45a2 , ptn , 2,8-sialyltranferase ) (Kobayashi et al, 1994; Kuroda et al, 2005; Kang et al, 2007; Zhang et al, 2013; Haltaufderhyde and Oancea 2014; Kimura et al, 2014; Liu et al, 2014; Morice-Picard et al, 2014; Choi et al, 2015; Eaton et al, 2015; Lindsay et al, 2015). The remaining two genes ( CA10 and kirrel3l ) are not well studied and their functions poorly charactrized.…”

Section: Resultsmentioning

confidence: 99%

Molecular genetic response of Xiphophorus maculatus–X. couchianus interspecies hybrid skin to UVB exposure

Bowswell

et al. 2015

Comparative Biochemistry and Physiology Part C: Toxicology &

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The phenotypic and genetic similarities between Xiphophorus and human melanoma render Xiphophorus a useful animal model for studying the genetic basis of melanoma etiology. In the Xiphophorus model, melanoma has been shown to be inducible by ultraviolet light (UVB) exposure among interspecies hybrids, but not in parental line fish similarly treated. This leads to questions of what genes are responsive to UVB exposure in the skin of the interspecies hybrids, as well as how parental alleles in hybrids may be differentially regulated and the potential roles they may play in induced melanomagenesis. To address these questions, we produced X. maculatus Jp 163 B × X. couchianus (Sp-Couch) F1 hybrid fish, exposed both hybrid and parental fish to UVB, and performed gene expression profiling of the skin using RNA-Seq methodology. We characterized a group of unique UVB-responsive genes in Sp-Couch hybrid including dct, pmela, tyr, tyrp1a, slc2a11b, rab38a, rab27, tspan10, slc45a2, oca2, slc24a5, ptn and mitfa. These genes are associated with melanin production and melanocyte proliferation. They were also up-regulated in Sp-Couch hybrid, indicating their UVB response is hybridization initiated. In the hybrid, several melanin production and pigmentation related genes, including slc45a2, tspan10, dct, slc2a11b and ptn showed either X. couchianus or X. maculatus allele specific expression. The finding that these genes exhibit allele specific expression regulatory mechanisms in Sp-Couch hybrids, but do not exhibit a corresponding UVB response in either one of the parental fishes, may suggest UVB targets and imply mechanisms regarding the susceptibility of Sp-Couch to induced melanomagenesis.

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Genome-wide transcriptome analysis of human epidermal melanocytes

Cited by 37 publications

References 64 publications

The human non-visual opsin OPN3 regulates pigmentation of epidermal melanocytes through interaction with MC1R

The human non-visual opsin OPN3 regulates pigmentation of epidermal melanocytes through interaction with MC1R

Human nonvisual opsin 3 regulates pigmentation of epidermal melanocytes through functional interaction with melanocortin 1 receptor

Molecular genetic response of Xiphophorus maculatus–X. couchianus interspecies hybrid skin to UVB exposure

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