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Title: Investigation of candidate imprinted tumour suppressor genes
Author: Judson, Hannah
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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Imprinting is an epigenetic phenomenon that silences one allele of a gene, so that expression in one or more cell types is exclusively monoallelic, and dependent on parental origin. Approaches used to identify novel imprinted genes rely on characteristic features such as the clustering of imprinted genes, or their association with differentially methylated CpG islands. An imprinted tumour suppressor gene involved in pathogenesis of neuroblastoma is believed to lie within chromosome 1p36. In this region, a search was initiated for imprinted genes in the vicinity of the imprinted gene TP73. The DFFB gene, encoding the apoptotic nuclease DNA fragmentation factor, was identified, and its intron-exon structure was elucidated. A pseudogene was also identified on chromosome 9. The tumour suppressor candidacy of DFFB was assessed through a comprehensive mutation screen of 42 neuroblastoma DNAs. No tumour-specific mutations were identified. Imprinting was then assessed by RT-PCR, which revealed biallelic expression of DFFB. It is unlikely that DFFB acts as a tumour suppressor in neuroblastoma. During a systematic screen, a differentially methylated CpG island, NV149, had been identified. In the present study, this locus was mapped to 6q24. The nearest gene was found to be the cell-cycle control gene, ZAC. Monallelic expression of ZAC from the paternal allele only was demonstrated in a range of fetal tissues. ZAC may possess a dual role in disease, such that upregulation by paternal duplication or paternal uniparental disomy of chromosome 6 results in transient neonatal diabetes mellitus (TNDM), whereas loss or down regulation of ZAC results in a loss of cell cycle control, and hence tumorigenesis. Through analysis of a panel of B cell lymphomas, evidence was found for hypermethylation of the NV149 CpG island, which may be one mechanism through which expression of ZAC is lost in tumours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available