Post-fertilization transcription initiation in an ancestral LTR retrotransposon drives lineage-specific genomic imprinting of ZDBF2

The imprinted gene ZDBF2 is regulated through a unique mechanism involving a transient paternal transcript in early embryos, rather than persistent gametic DNA methylation. In humans and mice, this transcript— CMKLR2-AS (also known as GPR1-AS ) or the long isoform of Zdbf2 ( Liz/Zdbf2linc/Platr12 )—arises from the unmethylated paternal allele and initiates secondary epigenetic marks that maintain ZDBF2 expression. Here, we investigate the evolutionary origin of this mechanism, and show that the first exon of human GPR1-AS overlaps with a MER21C long terminal repeat (LTR), a retrotransposon subfamily specific to Boreoeutherian mammals. Comparative analyses revealed that this MER21C insertion occurred in the common ancestor of Euarchontoglires, including primates, rodents, and rabbits. Although not annotated, the first exon of mouse Liz displays conserved features with the MER21C-overlapping exon in humans. In rabbit and nonhuman primate placentas, GPR1-AS orthologs with LTR-embedded first exons were also identified. In contrast, in non-Euarchontoglire mammals such as cow and tammar wallaby, ZDBF2 is biallelically expressed, suggesting absence of imprinting. These findings suggest that ZDBF2 imprinting emerged in Euarchontoglires via MER21C insertion. Together with our prior work on LTR-driven imprinting in oocytes, our findings demonstrate that post-fertilization activation of retrotransposons can also drive lineage-specific acquisition of imprinting.

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Journal
eLife
Published
2025-06-02
DOI
https://doi.org/10.7554/elife.94502.3
Primary Topic
Genetic Syndromes and Imprinting
Type
article
Field-Weighted Citation Impact
0.00

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article

Post-fertilization transcription initiation in an ancestral LTR retrotransposon drives lineage-specific genomic imprinting of ZDBF2

Hisato Kobayashi, Masaaki Hayashi, Keisuke Tanaka, Hiroshi Nagashima et al.
eLife
Genetic Syndromes and Imprinting
article

Post-fertilization transcription initiation in an ancestral LTR retrotransposon drives lineage-specific genomic imprinting of ZDBF2

Hisato Kobayashi, Masaaki Hayashi, Keisuke Tanaka, Hiroshi Nagashima, Ayuko Uchikura, Kazuhiko Nakabayashi, Tomoya Takashima, Matthew C. Lorincz, Hitomi Matsunari, Toshihiro Kobayashi, So I Nagaoka, Hiroo Imai, Hiroshi Kiyonari, Manabu Kawahara, Shun Saito, Kazuki Kurimoto, Mari Kaneko, Marilyn B. Renfree, Soichiro Kumamoto, Shunsuke Suzuki, Tatsushi Igaki, Kazuaki Nakano
article en

Abstract

The imprinted gene ZDBF2 is regulated through a unique mechanism involving a transient paternal transcript in early embryos, rather than persistent gametic DNA methylation. In humans and mice, this transcript— CMKLR2-AS (also known as GPR1-AS ) or the long isoform of Zdbf2 ( Liz/Zdbf2linc/Platr12 )—arises from the unmethylated paternal allele and initiates secondary epigenetic marks that maintain ZDBF2 expression. Here, we investigate the evolutionary origin of this mechanism, and show that the first exon of human GPR1-AS overlaps with a MER21C long terminal repeat (LTR), a retrotransposon subfamily specific to Boreoeutherian mammals. Comparative analyses revealed that this MER21C insertion occurred in the common ancestor of Euarchontoglires, including primates, rodents, and rabbits. Although not annotated, the first exon of mouse Liz displays conserved features with the MER21C-overlapping exon in humans. In rabbit and nonhuman primate placentas, GPR1-AS orthologs with LTR-embedded first exons were also identified. In contrast, in non-Euarchontoglire mammals such as cow and tammar wallaby, ZDBF2 is biallelically expressed, suggesting absence of imprinting. These findings suggest that ZDBF2 imprinting emerged in Euarchontoglires via MER21C insertion. Together with our prior work on LTR-driven imprinting in oocytes, our findings demonstrate that post-fertilization activation of retrotransposons can also drive lineage-specific acquisition of imprinting.

eLifeVol. 13
Kanazawa University (JP), Tokyo University of Agriculture (JP), Shinshu University (JP), University of British Columbia (CA), Tokyo University of Information Sciences (JP), Waseda University (JP), Tokyo University of Science (JP), The University of Melbourne (AU), Meiji University (JP), Hokkaido University (JP), Kyoto University (JP), RIKEN Center for Biosystems Dynamics Research (JP), National Center For Child Health and Development (JP), National Institute for Physiological Sciences (JP), Genetic Analysis (Norway) (NO), Nara Medical University (JP), The University of Tokyo (JP), Dokkyo Medical University (JP)
Takeda Science Foundation, Mitsubishi Foundation, Canadian Institutes of Health Research, Japan Society for the Promotion of Science
Openalex Percentile: Top 86%
Genetic Syndromes and Imprinting
DOIOpen Access PDFOpenAlex
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