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Every cell in the human body has a unique set of somatic mutations, but it remains difficult to comprehensively genotype an individual cell 1 . Here we describe ways to overcome this obstacle in the context of normal human skin, thus offering a glimpse into the genomic landscapes of individual melanocytes from human skin. As expected, sun-shielded melanocytes had fewer mutations than sun-exposed melanocytes. However, melanocytes from chronically sun-exposed skin (for example, the face) had a lower mutation burden than melanocytes from intermittently sun-exposed skin (for example, the back). Melanocytes located adjacent to a skin cancer had higher mutation burdens than melanocytes from donors without skin cancer, implying that the mutation burden of normal skin can be used to measure cumulative sun damage and risk of skin cancer. Moreover, melanocytes from healthy skin commonly contained pathogenic mutations, although these mutations tended to be weakly oncogenic, probably explaining why they did not give rise to discernible lesions. Phylogenetic analyses identified groups of related melanocytes, suggesting that melanocytes spread throughout skin as fields of clonally related cells that are invisible to the naked eye. Overall, our results uncover the genomic landscapes of individual melanocytes, providing key insights into the causes and origins of melanoma. A combination of clonal expansion and DNA amplification is used to sequence genetic material from individual melanocytes, shedding light on the mutational landscape of these cells and the development of melanomas.

Melanin, the pigment produced by specialized cells, melanocytes, is responsible for skin and hair color. Skin pigmentation is an important protective mechanism against the DNA damaging and mutagenic effects of solar ultraviolet radiation (UV). It is acknowledged that exposure to UV is the main etiological environmental factor for all forms of skin cancer, including melanoma. DNA repair capacity is another major factor that determines the risk for skin cancer. Human melanocytes synthesize eumelanin, the dark brown form of melanin, as well as pheomelanin, which is reddish-yellow in color. The relative rates of eumelanin and pheomelanin synthesis by melanocytes determine skin color and the sensitivity of skin to the drastic effects of solar UV. Understanding the complex regulation of melanocyte function and how it responds to solar UV has a huge impact on developing novel photoprotective strategies to prevent skin cancer, particularly melanoma, the most fatal form, which originates from melanocytes. This review provides an overview of the known differences in the photoprotective effects of eumelanin versus pheomelanin, how these two forms of melanin are regulated genetically and biochemically, and their impact on the DNA damaging effects of UV exposure. Additionally, this review briefly discusses the role of paracrine factors, focusing on α-melanocortin (α-melanocyte stimulating hormone; α-MSH), in regulating melanogenesis and the response of melanocytes to UV, and describes a chemoprevention strategy based on targeting the melanocortin 1 receptor (MC1R) by analogs of its physiological agonist α-MSH.

Skin is a major target of oxidative stress. Increasing evidence suggests that oxidative stress is the cause of melanocyte disappearance in vitiligo, which is an acquired pigmentary skin disorder characterized by patches of skin that have lost pigmentation. New herbal extracts with antioxidant activity are therefore being studied. 6-Shogaol (6-SG), an active compound from ginger, is capable of attenuating oxidative stress-induced ageing and neurotoxicity. Subsequently, to investigate whether 6-SG could protect melanocytes from oxidative stress, cultured human primary epidermal melanocytes (HEMn-MPs) were treated with hydrogen peroxide (H2O2) in the presence or absence of 6-SG. The 6-SG exhibited protective effects against H2O2-induced cell death by reducing oxidative stress. In addition, the 6-SG treatment activated the Nrf2-antioxidant response element signaling pathway by upregulating the mRNA expression of the antioxidant enzyme heme oxygenase 1 (HO-1), and protein expression of Nrf2, NAD(P)H: quinine oxidoreductase 1 (Nqo1), and HO-1. Furthermore, the 6-SG also displayed protective effects on melanocytes against Rhododendrol-induced oxidative stress. We concluded that 6-SG protects melanocytes against oxidative stress in vitro, and its protective effect is associated with the activation of the Nrf2-antioxidant response element signaling pathway. 6-SG, therefore, has potential for use in the prevention of melanocyte loss in the early stages of vitiligo or other pigmentary disorders.

Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD⁺) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD⁺ precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmdmdx/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD⁺ may reprogram dysfunctional SCs and improve life span in mammals.

The skin serves as a physical barrier and an immunological interface that protects the body from the external environment 1 – 3 . Aberrant activation of immune cells can induce common skin autoimmune diseases such as vitiligo, which are often characterized by bilateral symmetric lesions in certain anatomic regions of the body 4 – 6 . Understanding what orchestrates the activities of cutaneous immune cells at an organ level is necessary for the treatment of autoimmune diseases. Here we identify subsets of dermal fibroblasts that are responsible for driving patterned autoimmune activity, by using a robust mouse model of vitiligo that is based on the activation of endogenous auto-reactive CD8 + T cells that target epidermal melanocytes. Using a combination of single-cell analysis of skin samples from patients with vitiligo, cell-type-specific genetic knockouts and engraftment experiments, we find that among multiple interferon-γ (IFNγ)-responsive cell types in vitiligo-affected skin, dermal fibroblasts are uniquely required to recruit and activate CD8 + cytotoxic T cells through secreted chemokines. Anatomically distinct human dermal fibroblasts exhibit intrinsic differences in the expression of chemokines in response to IFNγ. In mouse models of vitiligo, regional IFNγ-resistant fibroblasts determine the autoimmune pattern of depigmentation in the skin. Our study identifies anatomically distinct fibroblasts with permissive or repressive IFNγ responses as the key determinant of body-level patterns of lesions in vitiligo, and highlights mesenchymal subpopulations as therapeutic targets for treating autoimmune diseases. Single-cell analyses of skin samples from patients with vitiligo and functional genetic experiments in vitiligo mouse models show that distinct fibroblast subsets drive the organ level lesion patterns in this autoimmune disease.

Certain transcription factors have vital roles in lineage development, including specification of cell types and control of differentiation. Microphthalmia-associated transcription factor (MITF) is a key transcription factor for melanocyte development and differentiation. MITF regulates expression of numerous pigmentation genes to promote melanocyte differentiation, as well as fundamental genes for maintaining cell homeostasis, including genes encoding proteins involved in apoptosis (eg, BCL2) and the cell cycle (eg, CDK2). Loss-of-function mutations of MITF cause Waardenburg syndrome type IIA, whose phenotypes include depigmentation due to melanocyte loss, whereas amplification or specific mutation of MITF can be an oncogenic event that is seen in a subset of familial or sporadic melanomas. In this article, we review basic features of MITF biological function and highlight key unresolved questions regarding this remarkable transcription factor.

Extrinsic skin aging is driven by environmental factors, including ultraviolet (UV) radiation and air pollution. While melanocytes serve as key protectors against UV-induced damage, their role in aging, particularly through the process of senescence, remains underexplored. Here, we exposed human neonatal melanocytes and ex vivo skin explants to UV (UVA + UVB), urban particulate matter (UPM), and their combination (UV + UPM) to assess the effects on melanocyte function and skin aging. We demonstrate that combined UV + UPM exposure triggers oxidative stress, mitochondrial and DNA damage, senescence, apoptosis, and modulation of melanogenesis in human neonatal melanocytes. In addition, skin explants subjected to the same treatments showed hallmark features of aging, including epidermal thinning, barrier disruption, fibrosis, and altered pigmentation. These findings highlight that melanocytes respond to environmental stress through multiple interconnected mechanisms, potentially affecting both cell survival and pigmentary function. Our model offers a useful platform to study how environmental stressors affect melanocyte function and skin biology, potentially supporting the development of future strategies targeting pigmentation disorders and environmentally driven skin aging.

Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs) 1 , 2 , but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics 3 , 4 , cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism. Stress induces hair greying in mice through depletion of melanocyte stem cells, which is mediated by the activation of sympathetic nerves rather than through immune attack or adrenal stress hormones.

Uveal melanoma (UM) is the most common primary intraocular cancer in adults. In the present study, we aimed to characterize the immunological features of primary UM cancer and to provide an association with prognostic markers and outcome. Also, we assessed the influence of the microenvironment on the expression of inhibitory immune checkpoints in UM. Genes of interest included MHC Class I and Class II molecules, as well as inhibitory immune-checkpoints, i.e. PDL1, PDL2, B7-H3, B7-H4, TBFRSF6B, CD47, CD155, GAL9, HVEM and CD200. We observed significant lower levels of MHC genes in UM cells as compared to normal uveal melanocytes. Unexpectedly however, the expression levels of most of the analyzed inhibitory immune-checkpoint genes were not different in cancer cells as compared to normal melanocytes, with the exception of CD200 and HVEM, that resulted significantly reduced. On the other hand, PDL1 inversely correlated with OS, PFS and thickness of the tumor. Also, PDL1, along with PDL2, expression significantly increased under inflammatory conditions. Finally, for the first time, we propose a possible role for CD47 in the immune evasive properties of UM. We show here that CD47 is significantly upregulated by UM cells following inflammatory stimuli and that it represents a good independent predictor of disease progression. The results from this study may propel advances in the development of immune-based therapies for UM patients.

Oncogenes BRAF(V600E) and SETDB1 in melanoma Transgenic zebrafish carrying the human oncogene BRAF(V600E) , the most common mutation in melanoma patients, provide a convenient model for melanoma. Two papers from Leonard Zon and colleagues demonstrate the potential of this system in the study of cancer genetics and in drug development. Ceol et al . screen for genes that cooperate with mutated BRAF , and identify SETDB1 as capable of accelerating melanoma formation in fish. The gene is found in a region that is frequently amplified in human melanomas, and its gene product, SETDB1, is a histone methylating enzyme that is often overexpressed in those melanomas. This work establishes SETDB1 as an important oncogene. White et al . find expression of a gene signature in melanoma-susceptible zebrafish embryos that is indicative of disrupted differentiation of neural crest progenitors. A chemical screen identifies leflunomide, an immunomodulatory drug used to treat rheumatoid arthritis, as an inhibitor of neural crest stem cells. Leflunomide has antimelanoma activity in human melanoma xenografts and might prove useful as an anticancer drug, particularly in combination with BRAF inhibitors. Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of HOX genes. The most common mutation in human melanoma, BRAF(V600E) , activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway 1 , 2 . BRAF(V600E) mutations are also present in benign melanocytic naevi 3 , highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes 4 , 5 . For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.