Logo image
Back
TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF
Journal article   Open access   Peer reviewed

TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF

Hannah E Seberg, Eric Van Otterloo, Stacie K Loftus, Huan Liu, Greg Bonde, Ramakrishna Sompallae, Derek E Gildea, Juan F Santana, J Robert Manak, William J Pavan, …
PLoS genetics, Vol.13(3), e1006636
03/2017
DOI: 10.1371/journal.pgen.1006636
PMCID: PMC5352137
PMID: 28249010
url
https://doi.org/10.1371/journal.pgen.1006636View
Published (Version of record) Open Access

Abstract

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.
 Mutation Humans Embryo, Nonmammalian - metabolism Embryo, Nonmammalian - embryology Melanocytes - metabolism Transcription Factor AP-2 - metabolism Embryo, Mammalian - metabolism Cell Differentiation - genetics Pigmentation - genetics RNA Interference Gene Expression Regulation, Developmental Base Sequence Cell Line Microphthalmia-Associated Transcription Factor - metabolism Zebrafish Proteins - metabolism Cells, Cultured Gene Expression Profiling - methods Zebrafish Binding Sites - genetics Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Nucleic Acid Mice, Knockout Microscopy, Confocal Transcription Factor AP-2 - genetics Animals Embryo, Mammalian - embryology Cell Line, Tumor Zebrafish Proteins - genetics Microphthalmia-Associated Transcription Factor - genetics

Details

Metrics

22 Record Views
60 Times Cited - Web of Science
Logo image