title: The Gpr1/Zdbf2 locus provides new paradigms for transient and dynamic genomic imprinting in mammals.
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.
authors.affiliation: INSERM U934/CNRS UMR3215, Institut Curie, 75005 Paris, France;
authors.forename: Rachel
authors.initials: R
authors.lastname: Duffié
authors.forename: Sophie
authors.initials: S
authors.lastname: Ajjan
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Greenberg
authors.forename: Natasha
authors.initials: N
authors.lastname: Zamudio
authors.forename: Martin
authors.initials: M
authors.lastname: Escamilla del Arenal
authors.forename: Julian
authors.initials: J
authors.lastname: Iranzo
authors.forename: Ikuhiro
authors.initials: I
authors.lastname: Okamoto
authors.forename: Sandrine
authors.initials: S
authors.lastname: Barbaux
authors.forename: Patricia
authors.initials: P
authors.lastname: Fauque
authors.forename: Déborah
authors.initials: D
authors.lastname: Bourc'his
mesh_terms: D000818:Animals; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism; D019143:Evolution, Molecular; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008322:Mammals / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D013091:Spermatogenesis / Q000235:genetics
chemical_list: D006657:Histones; D043562:Receptors, G-Protein-Coupled
keywords: DNA methylation; epigenetics; genomic imprinting; mouse development