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Genome-wide transcriptional profiling of Nf1-haploinsufficiency in mouse

ABSTRACT: Neurofibromatosis type 1 (NF1) is a common monogenic tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Haploinsufficiency of NF1 fosters a permissive tumorigenic environment through changes in signalling between cells; however, the intracellular mechanisms for this tumor-promoting effect are less clear. We hypothesized that the genetic effects of NF1-haploinsufficiency may be discerned by comparison of genome-wide transcriptional profiling in somatic, non-tumor cells from NF1-affected and –unaffected individuals. As a cross-species filter for heterogeneity, we compared the results from two human kindreds to whole-genome transcriptional profiling in spleen-derived B-cells from age- and gender-matched Nf1+/- and wild-type mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE18447 | GEO | 2009/11/30

SECONDARY ACCESSION(S): PRJNA123323

REPOSITORIES: GEO

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Genome-wide transcriptional profiling of NF1-haploinsufficiency in human: ECACC kindred

Project description:Neurofibromatosis type 1 (NF1) is a common monogenic tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Haploinsufficiency of NF1 fosters a permissive tumorigenic environment through changes in signalling between cells; however, the intracellular mechanisms for this tumor-promoting effect are less clear. We hypothesized that the genetic effects of NF1-haploinsufficiency may be discerned by comparison of genome-wide transcriptional profiling in somatic, non-tumor cells (LCLs) from NF1-affected and –unaffected individuals.

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Genome-wide transcriptional profiling of NF1-haploinsufficiency in human: Coriell kindred

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Transcription profiling of human NF1 heterozygous (NF1+/-) melanocytes from a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient

Project description:One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary café-au-lait macules where dysregulation of melanocyte development, proliferation and differentiation is considered to play a key etiopathogenic role. To gain better insight in 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 and hyperpigmented lesional café-au-lait skin. Out of 13,850 unique genes, a total of 137 had a significant twofold or more up- (72) or down-regulated (65) expression in NF1+/- melanocytes compared to NF1+/+ melanocytes (genotype effect). Considering possible intrinsic genetic variation in lesional skin, melanocytes showed a total of 51 genes having a significant twofold or more up- (37) or down-regulated (14) expression when they were cultured from hyperpigmentary café-au-lait skin compared to normally pigmented skin (lesional skin type effect). NF1+/- café-au-lait skin melanocytes showed 468 genes with a significant two-fold or more up- (183) or down-regulated (285) expression going beyond the sum of the separate main effects (interaction). Detailed analysis enabled the identification of several modulated genes in NF1+/- (café-au-lait skin) melanocytes, mainly involved in controlling cell proliferation and cell maintenance, in cell adhesion and, surprisingly, in the immune response. An interesting finding was that a high number of transcription factor genes were differentially modulated, among which a specific subset - important in melanocyte-lineage development - showed downregulation in a transcriptional cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene.

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Molecular dissection of somatic NF1 pseudarthrosis

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