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English: Imprinted regulation of Igf2/H19 and Igf2r/Airn in mice and humans. (a) The Igf2 and H19 genes are reciprocally imprinted, with H19 and Igf2 being expressed maternally and paternally, respectively. CTCF binds the maternal H19 ICR and acts as an insulator sequestering enhancers to initiate maternal H19 transcription while also protecting the H19 ICR from methylation. Methylation on the paternal H19 ICR prevents CTCF binding and silences paternal transcription. Igf2 is only expressed paternally as a lack of CTCF binding in the paternal H19 ICR allows enhancers to activate the Igf2 promoter. DMR1 is a silencer that is inactivated by methylation while DMR2 is an enhancer that is activated by methylation. DMR1 and DMR2 are both methylated on the paternal allele, facilitating paternal Igf2 transcription and blocking maternal transcription. (b) CTCF mediates an intrachromosomal loop, which prevents DNA methylation of the H19 DMR and Igf2 DMRs, while facilitating H19 expression. (c) In mice, Igf2r is maternally expressed while the overlapping Airn antisense transcript is paternally expressed. Histone H3K4 methylation in the maternal Igf2r promoter (DMR1) initiates transcription, while DNA methylation and histone H3K9 methylation in the downstream Airn promoter region (DMR2) silences maternal Airn transcription. Activating H3K4 methylation at the paternal Airn promoter region initiates paternal transcription of the Airn transcript. The Airn transcript overlaps the Igf2r promoter and contributes to the silencing of the paternal Igf2r allele along with DNA methylation and histone H3K9 methylation. (d) In humans, Ifg2r is biallelically expressed. Activating H3K4 methylation is found in both the maternal and paternal promoter regions of Igf2r. While maternal-specific DNA methylation of DMR2 is maintained, there is no H3K4 methylation of paternal DMR2, preventing the transcription of the Airn transcript.