Deletion of a silencer element in Igf2 results in loss of imprinting independent of H19

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Abstract
Igf2 and H19 are closely linked, reciprocally imprinted genes on mouse distal chromosome 7. The paternally expressed Igf2 encodes a potent fetal growth factor and the maternally expressed H19 encodes a non-coding RNA (refs 1,2). Shared endoderm-specific enhancers 3′ to H19 are necessary for transcription of the maternal copy of H19 and the paternal copy of Igf2 (ref. 3), a chromatin boundary upstream of H19 preventing access of the enhancers to the maternal Igf2 promoters4,5,6,7,8. Mesoderm-specific control elements have not been identified, and the role of differentially methylated regions (DMRs) in Igf2 has not been addressed. Two DMRs in Igf2 are methylated on the active paternal allele, suggesting that they contain silencers9,10,11,12. Here we have deleted the DMR1 region in Igf2. Maternal transmission of the deletion results in biallelic expression of Igf2 in most mesodermally derived tissues without altering H19 imprinting or expression. Paternal or maternal transmission leads to continued postnatal transcription of Igf2, in contrast to the wild-type allele, which is silenced soon after birth. These results reveal a mesodermal silencer, which may be regulated by methylation and which has a major role in H19-independent expression and imprinting control of Igf2. Our results establish a new mechanistic principle for imprinted genes whereby epigenetically regulated silencers interact with enhancers to control expression, and suggest a new mechanism for loss of imprinting (LOI) of Igf2, which may be important in a number of diseases.