Because melanocytes are dispensable for life, the melanocyte lineage can also serve as a model for investigation of developmental processes important in all cell types.
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Melanocytes are responsible for pigment deposition in skin and hair follicles, and the dysregulation of melanocyte differentiation underlies both pigmentation disorders and melanoma. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This work was supported in part by the National Human Genome Research Institute Intramural Research Program at the National Institutes of Health (DEG, SKL, and WJP). TFAP2A ChIP-seq data in mouse immortalized melanocytes is available at GEO, accession number GSE72953.įunding: This work was supported by: National Institutes of Health (AR062547, RAC) (DE12728, TW), the National Science Foundation (IOS-1147221, RAC), the University of Iowa Melanoma Research Fund (RAC), and fellowship F32DE023709 from the National Institute of Dental and Craniofacial Research (EVO).
The work is made available under the Creative Commons CC0 public domain dedication.ĭata Availability: TFAP2A ChIP-seq data in human primary melanocytes are available at GEO, accession number GSE67555.
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This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Received: OctoAccepted: FebruPublished: March 1, 2017 Barsh, Stanford University School of Medicine, UNITED STATES
(2017) TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.Ĭitation: Seberg HE, Van Otterloo E, Loftus SK, Liu H, Bonde G, Sompallae R, et al. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. These elements are also frequently bound by MITF, which is considered the “master regulator” of melanocyte development. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear.
Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans.