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The ZIC1 gene is expressed in early undifferentiated embryonic stem cells, subsequently down-regulated at the onset of differentiation and eventually, it is exclusively expressed in neural tissues. The mechanism(s) controlling the dynamic expression of this early embryonic gene is not fully understood.

Desmoid tumours arise from a monoclonal proliferation of fascia or musculo-aponeurotic structures (fibroblast-like cells), due to oncogenic mutations in beta-catenin. Expression arrays revealed the consistent upregulation of the neural transcription factor ZIC1, a member of the Zic family genes, in primary desmoid cultures when compared to primary fascia cultures. ZIC1 expression was also found in other fibroproliferative disorders, in activated fibroblasts during wound healing, and proliferating skin fibroblast in culture, whereas it is absent in resting fibroblasts. We hypothesized that DNA methylation, a well known epigenetic regulator of gene expression, could play a role in the dynamic expression of the ZIC1 gene. ZIC1 expression as assessed by RT PCR could be induced five folds in fascia cells after treatment with the DNA methylation inhibitor 5-aza-2’-deoxycytidine (5-aza-dC). In addition, via bisulfite genomic sequencing we could show that the promoter region of ZIC1 is unmethylated in desmoid tumour in contrast to the adjacent fascia fibroblasts where ZIC1 is methylated. The impact of methylation of the promoter on the expression of the protein was also examined. This high level of methylation at the ZIC1 promoter fully corresponds with the lack of ZIC1 expression observed by RT-PCR in fascia cells.

To our knowledge, this is the first report describing a potential role for DNA methylation in the control of ZIC1 expression, through the study of its aberrant expression in desmoid tumours. This finding also sheds a light on how the expression of a subset of embryonic genes can be regulated during embryonic development.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA