A genome-wide genetic screen uncovers determinants of human pigmentation

• 成果类型: Article
• 署名作者: Bajpai, Vivek K.; Swigut, Tomek; Mohammed, Jaaved; Naqvi, Sahin; Arreola, Martin; Tycko, Josh; Kim, Tayne C.; Pritchard, Jonathan K.; Bassik, Michael C.; Wysocka, Joanna
• 署名单位: Stanford University; Stanford University; University of Oklahoma System; University of Oklahoma - Norman; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8602
• DOI: 10.1126/science.ade6289
• 发表日期: 2023-08-11
• 页码: 646-+
• 关键词: tumor-suppressor gene; melanosome biogenesis; stem-cells; association; complex; colocalization; architecture; TRAFFICKING; expression; selection

摘要

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 ofmelanin-promoting genes, with broad implications for human variation, cell biology, and medicine.