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.

中文翻译：

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MC1R 抑制黑素细胞的单细胞分析

人类红发颜色 (RHC) 特征是由于黑皮质素 1 受体 (MC1R) 功能减弱，皮肤和头发中的褐黑素（红黄色）增加和真黑素（黑棕色）色素减少引起的。此外，具有 RHC 特征的个体容易患黑色素瘤。虽然MC1R变异已被确定为 RHC 的病因，并且是黑色素瘤的明确危险因素，但从机制上仍不清楚为什么 MC1R 信号传导减少会改变色素沉着并增加黑色素瘤易感性。在这里，我们使用从 RHC 小鼠模型中分离的黑素细胞的单细胞 RNA 测序 (scRNA-seq) 来定义 MC1R 抑制基因特征 (MiGS)，其中包含大量先前未识别的基因，这些基因可能与黑素生成和致癌转化有关。我们发现候选 MiGS 基因之一 TBX3（一种与黑色素瘤进展有关的众所周知的抗衰老转录因子）结合 E-box 和 T-box 元件来调节与黑色素生成和衰老旁路相关的基因。我们的结果提供了关于MC1R信号减弱的黑素细胞调节色素沉着的进一步机制的关键见解，并为了解具有RHC表型的个体如何易患黑色素瘤提供了新的研究候选者。