The Gpr1/Zdbf2 locus provides new paradigms for transient and dynamic genomic imprinting in mammals (original) (raw)

  1. Sophie Ajjan1,
  2. Maxim V. Greenberg1,
  3. Natasha Zamudio1,
  4. Martin Escamilla del Arenal1,
  5. Julian Iranzo1,
  6. Ikuhiro Okamoto1,4,
  7. Sandrine Barbaux2,
  8. Patricia Fauque3 and
  9. Déborah Bourc'his1,5
  10. 1INSERM U934/CNRS UMR3215, Institut Curie, 75005 Paris, France;
  11. 2INSERM U1016/CNRS UMR8104, Institut Cochin, 75005 Paris, France;
  12. 3Hôpital de Dijon, Laboratoire de Biologie de la Reproduction, Université de Bourgogne, 21000 Dijon, France

Abstract

Many loci maintain parent-of-origin DNA methylation only briefly after fertilization during mammalian development: Whether this form of transient genomic imprinting can impact the early embryonic transcriptome or even have life-long consequences on genome regulation and possibly phenotypes is currently unknown. Here, we report a maternal germline differentially methylated region (DMR) at the mouse Gpr1/Zdbf2 (DBF-type zinc finger-containing protein 2) locus, which controls the paternal-specific expression of long isoforms of Zdbf2 (Liz) in the early embryo. This DMR loses parental specificity by gain of DNA methylation at implantation in the embryo but is maintained in extraembryonic tissues. As a consequence of this transient, tissue-specific maternal imprinting, Liz expression is restricted to the pluripotent embryo, extraembryonic tissues, and pluripotent male germ cells. We found that_Liz_ potentially functions as both Zdbf2-coding RNA and _cis_-regulatory RNA. Importantly, _Liz_-mediated events allow a switch from maternal to paternal imprinted DNA methylation and from Liz to canonical Zdbf2 promoter use during embryonic differentiation, which are stably maintained through somatic life and conserved in humans. The Gpr1/Zdbf2 locus lacks classical imprinting histone modifications, but analysis of mutant embryonic stem cells reveals fine-tuned regulation of Zdbf2 dosage through DNA and H3K27 methylation interplay. Together, our work underlines the developmental and evolutionary need to ensure proper Liz/Zdbf2 dosage as a driving force for dynamic genomic imprinting at the Gpr1/Zdbf2 locus.

Footnotes