Related Experiment Video
Updated: Jul 11, 2025
Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model
Published on: September 7, 2013
Single-cell profiling of MC1R-inhibited melanocytes
H Matthew Berns1,2, Dawn E Watkins-Chow1, Sizhu Lu2
1Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
The human red hair color (RHC) trait is caused by increased pheomelanin (red-yellow) and reduced eumelanin (black-brown) pigment in skin and hair due to diminished melanocortin 1 receptor (MC1R) function. In addition, individuals harboring the RHC trait are predisposed to melanoma development. While MC1R variants have been established as causative of RHC and are a well-defined risk factor for melanoma, it remains unclear mechanistically why decreased MC1R signaling alters pigmentation and increases melanoma susceptibility. Here, we use single-cell RNA sequencing (scRNA-seq) of melanocytes isolated from RHC mouse models to define a MC1R-inhibited Gene Signature (MiGS) comprising a large set of previously unidentified genes which may be implicated in melanogenesis and oncogenic transformation. We show that one of the candidate MiGS genes, TBX3, a well-known anti-senescence transcription factor implicated in melanoma progression, binds both E-box and T-box elements to regulate genes associated with melanogenesis and senescence bypass. Our results provide key insights into further mechanisms by which melanocytes with reduced MC1R signaling may regulate pigmentation and offer new candidates of study toward understanding how individuals with the RHC phenotype are predisposed to melanoma.
Insights
Red hair color (RHC) is linked to lower melanocortin 1 receptor (MC1R) function, affecting pigment and increasing melanoma risk. This study identifies new genes, including TBX3, involved in RHC pigmentation and melanoma susceptibility.
Area of Science:
- Genetics
- Dermatology
- Molecular Biology
Background:
- The red hair color (RHC) trait results from reduced melanocortin 1 receptor (MC1R) function, leading to altered pigment production (increased pheomelanin, decreased eumelanin).
- Individuals with RHC have a higher predisposition to developing melanoma, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms linking diminished MC1R signaling to altered pigmentation and increased melanoma susceptibility.
- To identify novel genes regulated by MC1R signaling in melanocytes.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was performed on melanocytes from RHC mouse models.
- A MC1R-inhibited Gene Signature (MiGS) was defined.
- The role of candidate MiGS gene TBX3 in regulating melanogenesis and senescence was investigated.
Main Results:
- A novel MC1R-inhibited Gene Signature (MiGS) was identified, comprising numerous previously unrecognized genes.
- TBX3, an anti-senescence transcription factor, was identified as a key MiGS gene.
- TBX3 was shown to regulate genes involved in melanogenesis and senescence bypass by binding to specific DNA elements.
Conclusions:
- Reduced MC1R signaling impacts pigmentation and melanoma risk through a complex gene network, including TBX3.
- These findings provide new insights into the mechanisms underlying RHC and melanoma predisposition.
- TBX3 and other MiGS genes represent potential targets for future research into melanoma development in RHC individuals.
