Single-cell profiling of MC1R-inhibited melanocytes

IF 3.9 3区 医学 Q2 CELL BIOLOGY Pigment Cell & Melanoma Research Pub Date : 2023-11-16 DOI:10.1111/pcmr.13141
H. Matthew Berns, Dawn E. Watkins-Chow, Sizhu Lu, Pakavarin Louphrasitthiphol, Tongwu Zhang, Kevin M. Brown, Pedro Moura-Alves, Colin R. Goding, William J. Pavan
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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.

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mc1r抑制黑色素细胞的单细胞分析。
人类的红发色(RHC)特征是由于黑色素皮质素1受体(MC1R)功能减弱,皮肤和头发中的泛黑素(红黄色)增加,真黑素(黑棕色)减少造成的。此外,具有RHC特征的个体易患黑色素瘤。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,但仍不清楚MC1R信号减少改变色素沉着并增加黑色素瘤易感性的机制。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抑制基因签名(MiGS),其中包含大量先前未识别的基因,这些基因可能与黑素形成和致癌转化有关。我们发现候选MiGS基因之一TBX3是一种众所周知的与黑色素瘤进展有关的抗衰老转录因子,它结合E-box和T-box元件来调节与黑色素形成和衰老绕道相关的基因。我们的研究结果为进一步了解MC1R信号减少的黑素细胞可能调节色素沉着的机制提供了关键见解,并为理解具有RHC表型的个体如何易患黑色素瘤提供了新的研究候选人。
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来源期刊
Pigment Cell & Melanoma Research
Pigment Cell & Melanoma Research 医学-皮肤病学
CiteScore
8.90
自引率
2.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Pigment Cell & Melanoma Researchpublishes manuscripts on all aspects of pigment cells including development, cell and molecular biology, genetics, diseases of pigment cells including melanoma. Papers that provide insights into the causes and progression of melanoma including the process of metastasis and invasion, proliferation, senescence, apoptosis or gene regulation are especially welcome, as are papers that use the melanocyte system to answer questions of general biological relevance. Papers that are purely descriptive or make only minor advances to our knowledge of pigment cells or melanoma in particular are not suitable for this journal. Keywords Pigment Cell & Melanoma Research, cell biology, melatonin, biochemistry, chemistry, comparative biology, dermatology, developmental biology, genetics, hormones, intracellular signalling, melanoma, molecular biology, ocular and extracutaneous melanin, pharmacology, photobiology, physics, pigmentary disorders
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