Lineage-specific genomic imprinting driven by LTR-derived sequence activating after fertilization

The imprinted ZDBF2 gene is controlled by oocyte-derived DNA methylation, but its regulatory system is quite different from that of other canonically imprinted genes that are dependent on gamete DNA methylation. In the case of the ZDBF2 locus, maternal DNA methylation in the imprinted differentially methylated region (DMR) does not persist after implantation. Instead, a transient transcript from the unmethylated paternal allele of the DMR, known as GPR1-AS, contributes to establishing secondary DMRs that maintain the paternal expression of ZDBF2 in the somatic lineage. The imprinting of ZDBF2 and its unique regulatory system are conserved in humans and mice but are unknown in other mammals. Interestingly, the first exon of human GPR1-AS overlaps with that of MER21C, a subfamily of long terminal repeat (LTR) retrotransposons. Although this LTR appears and is amplified in eutherians, LTR insertion into the GPR1-AS orthologous region occurred in the common ancestor of Euarchontoglires, a clade that includes primates, rodents, and rabbits. Directional RNA sequencing of various mammalian species has identified GPR1-AS orthologs in rabbits and nonhuman primates, and their first exon overlapped with the same LTR. Furthermore, allele-specific expression analysis showed that bovine and tammar wallaby, mammals outside the Euarchontoglires group, expressed both alleles in all analyzed tissues. Our previous studies showed that LTRs reactivated in oocytes drive lineage-specific imprinting during mammalian evolution. The data presented here suggest that LTR-derived sequence activation after fertilization can also contribute to the lineage-specific establishment of imprinted genes.