Michael Sullivan
Cancer Genetics Laboratory, Department of Biochemistry; University of Otago
Genomic imprinting is a molecular process where only one allele of a gene is expressed depending upon the parent from which it was inherited (1). At present we are not sure why imprinting exists, and we are far from having a full understanding of the molecular events involved, however there is good evidence for DNA methylation having an important role. IGF2 is a fetal growth factor protein. The IGF2 gene is imprinted so only the paternally inherited allele is expressed. Adjacent to IGF2 is another imprinted gene, H19, that is expressed from the maternally inherited allele while the paternally allele is repressed. We have previously reported that in some Wilms' tumors there is relaxation of IGF2 imprinting and both alleles are expressed (biallelic expression) (2). Relaxation of IGF2 imprinting has since been found in many different solid tumors and in some leukemias.
Our previous methylation studies found loss of IGF2 imprinting was associated with loss of methylation from the repressed maternal IGF2 allele and inactivation of the maternally inherited H19 gene (3). In these tumors the maternally inherited IGF2 and H19 alleles have acquired a paternal methylation epigenotype.
We have now completed a detailed analysis of IGF2 methylation. In tumors with relaxed IGF2 imprinting there was loss of methylation from the repressed maternal allele over a 2kb region spanning exons 2 and 3. This pattern of methylation has implications for models of IGF2 and H19 imprinting. The current model in the mouse proposes a long-range competition exists between Ie and H19 for the activity of regional enhancer elements located downstream of the H19 gene. Central to this model is the presence of allele-specific methylation on the active paternal IGF2 allele. However, we have shown IGF2 imprinting in humans is associated with methylation of the repressed maternal allele. The human IGF2 gene has four promoters, three of which are imprinted. When IGF2 imprinting is lost all three imprinted promoters are biallelically expressed, This suggests there is a region upstream IGF2 which coordinates repression of the maternally inherited IGF2 allele. We are now using the bisulfite methylation method for a more detailed methylation analysis of the human IGF2 upstream region.
References:
Efstradiadis, A. Curr. Opin. Genet. 4: 265-280, 1994.
Ogawa, O., Eccles,M.R., Szeto,J., McNoe,L.A., Yun,K., Maw,M.A., Smith,P.J. and Reeve,A.E. Nature 362, 749-751, 1993.
Taniguchi, T., Sullivan,M.J., Ogawa,O. and Reeve,A.E. Proc. Natl. Acad. Sci. USA 92: 2159-2163, 1995.