MODULATION OF IGF2 GENOMIC IMPRINTING IN MICE INDUCED BY 5-AZACYTIDINE, AN INHIBITOR OF DNA METHYLATION

The adjacent genes, insulin-like growth factor 2 (Igf2) and H19, are i mprinted in both mouse and human. While Igf2 is expressed from the pat ernal allele, H19 is transcribed exclusively from the maternal allele. To explore the underlying mechanism of Igf2 and H19 imprinting, we st udied the effect of DNA demethylation on allelic expression by injecti ng mice with the demethylating agent 5-azacytidine (5-aza-C). We obser ved a greater than or equal to 22-fold increase in the abundance of Ig f2 mRNA in liver from treated mice compared with that of control mice. There was no significant change in Igf2 or H19 expression in brain. I n the 5-aza-C-treated mice, there was dramatic modulation of Igf2 impr inting. In some tissues, Igf2 was expressed biallelically, while in ot her tissues, the paternal allele was silenced and the normally imprint ed maternal allele was expressed, an example of allelic switching. The re was no change in the normal biallelic pattern of Igf2 expression in brain. H19, on the other hand, remained imprinted in all tissues in m ice treated with 5-aza-C. These results provide the first example of a pharmacological manipulation of genomic imprinting of an endogenous g ene in vivo and further implicate DNA methylation as an important fact or in maintaining the differential allelic expression of the Igf2 gene .