Imprinting of insulin-like growth factor 2 (IGF2) is thought to be controlled by DNA methylation of an imprinting control region (ICR) which lies on human chromosome 11 and mouse chromosome 7, upstream of the non-coding H19 gene. Essentially, when cytosines in the ICR are methylated (on the 5′ carbon of the pyrimidine ring), it prevents binding of CCCTC-binding factor (CTCF). CTCF is an insulator protein – by its binding, it prevents the enhancer region(E) from acting on the IGF2 gene and allowing expression. So, when the ICR region is metylated, the enahncer region can act, and IGF2 is expressed. In most normal tissues (with the major exception of liver tissue), IGF2 is only expressed from the paternally derived gene – as the paternal gene has a methylated ICR and the maternal ICR is unmethylated.
A known epigenetic defect is the loss of imprinting (LOI) of IGF2. Imprinting refers to parent-of-origin specific expression of genes – in the case of IGF2, expression is usually only from the paternal copy of the gene. When imprinting is lost, IGF2 is biallelically expressed, leading to a double-dose of IGF2. Since IGF2 is a potent mitogen, this can have a significant affect on cell growth, increasing the risk of cancer; specifically, loss of imprinting is implicated as a risk factor for colorectal cancer. It has been found that the colonic crypts – structures in the colonic epithelium – are significantly lengthened in individuals or model organisms with LOI. It is possible that this expansion of the dividing cells in the crypt epithelium provides a more fertile ground for cancer dvelopment (pictured to the left).
We found two interesting things about LOI of IGF2 using a mouse model: that LOI seems to alter the signal transduction pathways and that LOI seems to cause an “addiction” like behavior. Azoxymethane is a carcinogen which prompts the formation of aberrant crypt foci (ACF) in the mouse intestine. We found that LOI mice dosed with azoxymethane have significantly more ACFs than WT mice. When given a drug which inhibits the IGF2 pathway, the number of ACFs formed in WT mice remained unchanged, but the number of ACFs in LOI mice dropped to level below that of WT. This indicates that cancers evolving from LOI patients might be vulnerable to tailored therapies.