Gene expression profiling of cultured human NF1 heterozygous (NF1+/-) melanocytes reveals downregulation of a transcriptional cis-regulatory network mediating activation of the melanocyte-specific dopachrome tautomerase (DCT) gene.
One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary café-au-lait macules where disregulation of melanocyte biology is supposed to play a key etiopathogenic role. To gain better insight into the possible role of the tumor suppressor gene NF1, a transcriptomic microarray analysis was performed on human NF1 heterozygous (NF1+/-) melanocytes of a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient, both cultured from normally pigmented skin and hyperpigmented lesional café-au-lait skin. From the magnitude of gene effects, we found that gene expression was affected most strongly by genotype and less so by lesional type. A total of 137 genes had a significant twofold or more up- (72) or downregulated (65) expression in NF1+/- melanocytes compared with NF1+/+ melanocytes. Melanocytes cultured from hyperpigmented café-au-lait skin showed 37 upregulated genes whereas only 14 were downregulated compared with normal skin melanocytes. In addition, significant genotype xlesional type interactions were observed for 465 genes. Differentially expressed genes were mainly involved in regulating cell proliferation and cell adhesion. A high number of transcription factor genes, among which a specific subset important in melanocyte lineage development, were downregulated in the cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene. Although the results presented have been obtained with a restricted number of patients (one NF1 patient and one control) and using cDNA microarrays that may limit their interpretation, the data nevertheless addresses for the first time the effect of a heterozygous NF1 gene on the expression of the human melanocyte transcriptome and has generated several interesting candidate genes helpful in elucidating the etiopathology of café-au-lait macules in NF1 patients.
Boucneau
Joachim
J
Department of Dermatology, Ghent University, De Pintelaan 185, B-9000 Gent, Belgium.
De Schepper
Sofie
S
Vuylsteke
Marnik
M
Van Hummelen
Paul
P
Naeyaert
Jean-Marie
JM
Lambert
Jo
J
D002478:Cells, Cultured; D002877:Chromosomes, Human; D015536:Down-Regulation; D020869:Gene Expression Profiling; D016514:Genes, Neurofibromatosis 1 / Q000502:physiology*; D005838:Genotype; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008544:Melanocytes / Q000378:metabolism*; D009456:Neurofibromatosis 1 / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic
D025542:Neurofibromin 1; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase