GenesForLife wrote:This would be testable, I think, by looking for p16 methylation in children of smokers not themselves associated with smoking, at a very early stage in life, firstly, and by seeing if there is a statistical difference in children with both parents being smokers, if maternal imprinting could have something to do with it.

GenesForLife wrote:And oh, I must mention that this alone is often insufficient to trigger cancer, it is just one of the several things that must happen, including dedifferentiation, self sufficiency of mitogenesis, cell immortalization et cetera before it becomes cancerous.

* The mouse insulin-like growth factor type 2 receptor (Igf2r) is imprinted and expressed exclusively from the maternally inherited chromosome. To investigate whether methylation could function as the imprinting signal, we have cloned 130 kb from the Igf2r locus and searched for sequences methylated in a parental-specific manner. Two regions have been identified: region 1 contains the start of transcription and is methylated only on the silent paternal chromosome; region 2 is contained in an intron and is methylated only on the expressed maternal chromosome. Methylation of region 1 is acquired after fertilization, in contrast with the methylation of region 2, which is inherited from the female gamete. Methylation of region 2 may mark the maternal Igf2r locus in a manner that could act as an imprinting signal. These data suggest that the expressed locus carries a potential imprinting signal and imply that methylation is necessary for expression of the Igf2r gene.

Imprinting, the differential expression of the two alleles of a gene based on their parental origin, requires that the alleles be distinguished or marked. A candidate for the differentiating mark is DNA methylation. The maternally expressed H19 gene is hypermethylated on the inactive paternal allele in somatic tissues and sperm, but to serve as the mark that designates the imprint, differential methylation must also be present in the gametes and the pre−implantation embryo. We now show that the pattern of differential methylation in the 5' portion of H19 is established in the gametes and a subset is maintained in the pre−implanation embryo. That subset is sufficient to confer monoallelic expression to the gene in blastocysts. We propose that paternal−specific methylation of the far 5' region is the mark that distinguishes the two alleles of H19

Imprinted genes are epigenetically marked during gametogenesis so that they are exclusively expressed from either the paternal or the maternal allele in offspring1. Imprinting prevents parthenogenesis in mammals and is often disrupted in congenital malformation syndromes, tumours and cloned animals1. Although de novo DNA methyltransferases of the Dnmt3 family are implicated in maternal imprinting2, the lethality of Dnmt3a and Dnmt3b knockout mice3 has precluded further studies. We here report the disruption of Dnmt3a and Dnmt3b in germ cells, with their preservation in somatic cells, by conditional knockout technology4. Offspring from Dnmt3a conditional mutant females die in utero and lack methylation and allele-specific expression at all maternally imprinted loci examined. Dnmt3a conditional mutant males show impaired spermatogenesis and lack methylation at two of three paternally imprinted loci examined in spermatogonia. By contrast, Dnmt3b conditional mutants and their offspring show no apparent phenotype. The phenotype of Dnmt3a conditional mutants is indistinguishable from that of Dnmt3L knockout mice2, 5, except for the discrepancy in methylation at one locus. These results indicate that both Dnmt3a and Dnmt3L are required for methylation of most imprinted loci in germ cells, but also suggest the involvement of other factors.