Placental imprinting: Emerging mechanisms and functions

Abstract

As the maternal-foetal interface, the placenta is essential for the establishment and progression of healthy pregnancy, regulating both foetal growth and maternal adaptation to pregnancy. The evolution and functional importance of genomic imprinting are inextricably linked to mammalian placentation. Recent technological advances in mapping and manipulating the epigenome in embryogenesis in mouse models have revealed novel mechanisms regulating genomic imprinting in placental trophoblast, the physiological implications of which are only just beginning to be explored. This review will highlight important recent discoveries and exciting new directions in the study of placental imprinting.

Fig 1. Extraembryonic-specific imprinted genes in the mouse genome.

Genes reported to show imprinted gene expression almost exclusively in placenta and/or visceral endoderm [,,–40]. Red genes are maternally expressed, whereas blue genes are paternally expressed. Genes that are noncanonically imprinted are underlined. Asterisks mark genes that are imprinted by an alternative mechanism in somatic tissues.

Fig 2. Novel mechanisms of imprinted gene regulation in placenta.

There are several examples of imprinted loci that acquire different epigenetic patterning in postimplantation development between the placental trophoblast and epiblast: (A) Secondary imprinting, such as the Zdbf2 locus. Transient monoallelic transcription of the paternal Liz occurs in the preimplantation embryo, with the maternal allele being silenced by a gDMR. Because of traversing transcription, the epigenetic status of the paternal allele is remodelled in the epiblast, acquiring DNA methylation at the downstream sDMR and active H3K4me3 at the Zdbf2 promoter. Therefore, even though the maternal gDMR is reprogrammed and loses its imprinted status in the epiblast, Zdbf2 retains imprinted expression. In trophoblast, the maternal gDMR persists, and Liz continues to be paternally transcribed. (B) Large imprinted gene clusters, such as the Kcnq1ot1/Kcnq1 or Airn/Igf2r loci. A maternal gDMR silences the expression of an lncRNA, resulting in monoallelic expression from the paternal allele. The lncRNA associates with polycomb group proteins and potentially other epigenetic modifiers and/or repressive complexes, resulting in deposition of H3K27me3 along the paternal allele. In the epiblast, genes in relatively close proximity to the gDMR are silenced on the paternal allele because of acquisition of sDMRs at their respective promoters. In trophoblast, the silencing on the paternal allele is expansive, with H3K27me3 spreading along the paternal chromosome, silencing genes megabases away. (C) Noncanonical imprinting, such as Gab1 and Sfmbt2 loci. Maternally inherited H3K27me3 silences the expression of ERVs, which become actively transcribed on the paternal allele in the preimplantation embryo. In the postimplantation epiblast, these ERVs are silenced by DNA methylation, resulting in a loss of imprinting in somatic lineages. Although maternal H3K27me3 is lost, DNA methylation is acquired on the maternal allele in trophoblast, resulting in the generation of an sDMR. Hence, monoallelic paternal expression of noncanonically imprinted ERVs is maintained in trophoblast, which can confer imprinting of nearby protein-coding genes. Airn, antisense of Igf2r nonprotein coding RNA; ERV, endogenous retrovirus; gDMR, germline differentially methylated region; H3K4me3, histone 3 lysine 4 trimethylation; Igf2r, insulin-like growth factor 2 receptor; Kcnq1, potassium voltage-gated channel subfamily Q member 1; Kcnq1ot1, KCNQ1 opposite strand/antisense transcript 1; Liz, long isoform of Zdbf2; lncRNA, long noncoding RNA; sDMR, secondary differentially methylated region; Sfmbt2, Scm like with four mbt domains 2; Zdbf2, zinc finger DBF-type containing 2.

Fig 3. Function of placental-specific imprinting.

(A) The localisation of trophoblast cell types in an E12.5 mouse placenta. The syncytiotrophoblast forms the labyrinth layer, in which nutrient, waste, and gas exchange occurs between maternal and foetal circulations. The spongiotrophoblast, glycogen, and trophoblast giant cells form the junctional zone, which is essential in hormone production to support foetal growth and maternal adaptations to pregnancy. (B) Placental-specific imprinted genes have the capacity to regulate both maternal and foetal physiology. The placenta releases a number of factors into maternal circulation, including exosomes, hormones, nucleic acids, and proteins, many of which have been shown to be essential in the maternal adaptations to pregnancy. In turn, placentation can directly regulate nutrient uptake, as well as through the production of growth hormones, to support foetal development. E, embryonic day.