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PGC-1 coactivators regulate MITF and the tanning response.

ABSTRACT: The production of pigment by melanocytes tans the skin and protects against skin cancers. UV-exposed keratinocytes secrete ?-MSH, which then activates melanin formation in melanocytes by inducing the microphthalmia-associated transcription factor (MITF). We show that PPAR-? coactivator (PGC)-1? and PGC-1? are critical components of this melanogenic system in melanocytes. ?-MSH signaling strongly induces PGC-1? expression and stabilizes both PGC-1? and PGC-1? proteins. The PGC-1s in turn activate the MITF promoter, and their expression correlates strongly with that of MITF in human melanoma cell lines and biopsy specimens. Inhibition of PGC-1? and PGC-1? blocks the ?-MSH-mediated induction of MITF and melanogenic genes. Conversely, overexpression of PGC-1? induces pigment formation in cell culture and transgenic animals. Finally, polymorphism studies reveal expression quantitative trait loci in the PGC-1? gene that correlate with tanning ability and protection from melanoma in humans. These data identify PGC-1 coactivators as regulators of human tanning.

SUBMITTER: Shoag J

PROVIDER: S-EPMC3753666 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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PGC-1 coactivators regulate MITF and the tanning response.

Shoag Jonathan J Haq Rizwan R Zhang Mingfeng M Liu Laura L Rowe Glenn C GC Jiang Aihua A Koulisis Nicole N Farrel Caitlin C Amos Christopher I CI Wei Qingyi Q Lee Jeffrey E JE Zhang Jiangwen J Kupper Thomas S TS Qureshi Abrar A AA Cui Rutao R Han Jiali J Fisher David E DE Arany Zoltan Z

Molecular cell 20121129 1

The production of pigment by melanocytes tans the skin and protects against skin cancers. UV-exposed keratinocytes secrete α-MSH, which then activates melanin formation in melanocytes by inducing the microphthalmia-associated transcription factor (MITF). We show that PPAR-γ coactivator (PGC)-1α and PGC-1β are critical components of this melanogenic system in melanocytes. α-MSH signaling strongly induces PGC-1α expression and stabilizes both PGC-1α and PGC-1β proteins. The PGC-1s in turn activate ...[more]

PMID: 23201126

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Project description:Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. 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. 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. These elements are also frequently bound by MITF, which is considered the "master regulator" of melanocyte development. 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. 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. 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. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. 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. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.

Dataset Information

PGC-1 coactivators regulate MITF and the tanning response.

Publications

PGC-1 coactivators regulate MITF and the tanning response.

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