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Science (New York, N.Y.) Aug 2023Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering...
Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes that converge on melanosome biogenesis, endosomal transport, and gene regulation, of which 135 represented previously unknown associations with pigmentation. In agreement with their melanin-promoting function, the majority of screen hits were up-regulated in melanocytes from darkly pigmented individuals. We further unraveled functions of KLF6 as a transcription factor that regulates melanosome maturation and pigmentation in vivo, and of the endosomal trafficking protein COMMD3 in modulating melanosomal pH. Our study reveals a plethora of melanin-promoting genes, with broad implications for human variation, cell biology, and medicine.
Topics: Humans; Melanins; Melanocytes; Melanosomes; Skin Pigmentation; Genome-Wide Association Study; Adaptor Proteins, Signal Transducing; Kruppel-Like Factor 6; Endosomes; Animals; Mice; Cell Line, Tumor
PubMed: 37561850
DOI: 10.1126/science.ade6289 -
Cell Jan 2024To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture of the treatment-naive...
To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture of the treatment-naive melanoma ecosystem and studied its evolution under ICB. Using single-cell, spatial multi-omics, we showed that the tumor microenvironment promotes the emergence of a complex melanoma transcriptomic landscape. Melanoma cells harboring a mesenchymal-like (MES) state, a population known to confer resistance to targeted therapy, were significantly enriched in early on-treatment biopsies from non-responders to ICB. TCF4 serves as the hub of this landscape by being a master regulator of the MES signature and a suppressor of the melanocytic and antigen presentation transcriptional programs. Targeting TCF4 genetically or pharmacologically, using a bromodomain inhibitor, increased immunogenicity and sensitivity of MES cells to ICB and targeted therapy. We thereby uncovered a TCF4-dependent regulatory network that orchestrates multiple transcriptional programs and contributes to resistance to both targeted therapy and ICB in melanoma.
Topics: Humans; Gene Regulatory Networks; Immunotherapy; Melanocytes; Melanoma; Transcription Factor 4; Tumor Microenvironment
PubMed: 38181739
DOI: 10.1016/j.cell.2023.11.037 -
International Journal of Biological... 2023Hair graying is a common and visible sign of aging resulting from decreased or absence of melanogenesis. Although it has been established that gray hair greatly impacts... (Review)
Review
Hair graying is a common and visible sign of aging resulting from decreased or absence of melanogenesis. Although it has been established that gray hair greatly impacts people's mental health and social life, there is no effective countermeasure other than hair dyes. It has long been thought that reversal of gray hair on a large scale is rare. However, a recent study reported that individual gray hair darkening is a common phenomenon, suggesting the possibility of large-scale reversal of gray hair. In this article, we summarize the regulation mechanism of melanogenesis and review existing cases of hair repigmentation caused by several factors, including monoclonal antibodies drugs, tyrosine kinase inhibitors (TKIs), immunomodulators, other drugs, micro-injury, and tumors, and speculate on the mechanisms behind them. This review offers some insights for further research into the modulation of melanogenesis and presents a novel perspective on the development of clinical therapies, with emphasis on topical treatments.
Topics: Humans; Hair; Hair Color; Hair Follicle; Melanocytes; Pigmentation; Administration, Topical; Mental Health
PubMed: 37781032
DOI: 10.7150/ijbs.86911 -
Dermatology Practical & Conceptual Dec 2023Vitiligo is a chronic auto-immune disease characterized by skin depigmentation due to the loss of melanocytes. The better understanding of the disease mechanisms is... (Review)
Review
Vitiligo is a chronic auto-immune disease characterized by skin depigmentation due to the loss of melanocytes. The better understanding of the disease mechanisms is currently undergoing a significant dynamism, opening a new era in therapeutic development. The pathophysiology of vitiligo has attracted the attention of researchers for years and many advances have been made in clarifying the crosstalk between the cellular players involved in the development of vitiligo lesions. The understanding of the complex interactions between epidermal cells (i.e. melanocytes and keratinocytes), dermal fibroblasts, and immune cells, led to a better characterization of the signals leading to the loss of melanocytes. Recent advances highlighted the role resident T memory cells in the development and recurrence of lesions. This narrative review aims to give an overview of the mechanisms leading to melanocyte disappearance in vitiligo, with a focus on the intercellular interaction network involved in the activation of the local skin immune response.
PubMed: 38241397
DOI: 10.5826/dpc.1304S2a314S -
Theranostics 2023Senescent melanocytes accumulate in photoaged skin and are closely related to skin aging. A better understanding of the molecular characteristics of senescent...
Senescent melanocytes accumulate in photoaged skin and are closely related to skin aging. A better understanding of the molecular characteristics of senescent melanocytes may be the key to controlling skin aging. We have developed an model of senescence in melanocytes using UV irradiation and investigated the functional characteristics and molecular mechanisms underlying senescence in UV-irradiated melanocytes. We have highlighted that senescent melanocytes are characterized by melanosome transport dysfunction resulting in melanin accumulation. The defective melanosome transport was confirmed with the ultrastructural characterization of both UV-induced senescent melanocytes and melanocytes of hypopigmented aging skin. A single-cell transcriptomic analysis revealed that the glycolytic metabolism pathway appeared to be significantly upregulated in most senescent phenotypes. Furthermore, the inhibition of glycolysis by pharmacological compounds mitigates the pro-aging effects of melanocytes senescence, suggesting that alterations in cellular glucose metabolism act as a driving force for senescence in melanocytes. These results demonstrate that senescent melanocytes are characterized by glycolytic metabolism changes and a defective melanosome transport process, which may be related to impaired mitochondrial function, highlighting the importance of metabolic reprogramming in regulating melanocyte senescence.
Topics: Melanosomes; Melanocytes; Skin; Melanins; Glycolysis; Cellular Senescence
PubMed: 37554281
DOI: 10.7150/thno.84912