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.

Human Oocyte-Derived Methylation Differences Persist in the Placenta Revealing Widespread Transient Imprinting

“…To date all imprinted domains contain at least one differentially methylated region (DMR) that acquires methylation during gametogenesis (germline DMR, or gDMR), and maintained throughout development. Some imprinted loci also contain DMRs that become allelically methylated in the embryonic diploid genome (somatic DMRs, or sDMR) which are under the hierarchical influence of gDMRs [4, 9, 10]. Recently, transiently methylated germline DMRs (tDMRs) have been identified in mice that are indistinguishable from ubiquitous imprinted gDMRs in gametes and preimplantation embryos [11].…”

Lentiviral Vector-Mediated Complementation Restored Fetal Viability but Not Placental Hyperplasia in Plac1-Deficient Mice1

“…Recently, transient imprinting and aberrant allele switching have been implicated in developmental and disease-related phenotypes [16,17]. For example, during mammalian development, many loci maintain parent-of-origin DNA methylation only briefly after fertilization [16]. Antisense noncoding RNA has also been implicated in the imprint switch mechanism in breast cancers [17].…”

“…In the present study, by separating male and female blastocysts using an X egfp transgenic strain, we demonstrated that Plac1 gene is paternally expressed before implantation and then switched to be maternally expressed after implantation. Recently, transient imprinting and aberrant allele switching have been implicated in developmental and disease-related phenotypes [16,17]. For example, during mammalian development, many loci maintain parent-of-origin DNA methylation only briefly after fertilization [16].…”

Maternal residential air pollution and placental imprinted gene expression

“…ZDBF2 is a unique imprinted gene in that it contains both maternal and paternal marks (Duffie et al 2014). During the pre-implantation period and in the placenta after implantation, the maternal allele is silenced.…”