DNA Methylation Dynamics in the Female Germline and Maternal-Effect Mutations That Disrupt Genomic Imprinting

Abstract

Genomic imprinting is an epigenetic marking process that results in the monoallelic expression of a subset of genes. Many of these 'imprinted' genes in mice and humans are involved in embryonic and extraembryonic growth and development, and some have life-long impacts on metabolism. During mammalian development, the genome undergoes waves of (re)programming of DNA methylation and other epigenetic marks. Disturbances in these events can cause imprinting disorders and compromise development. Multi-locus imprinting disturbance (MLID) is a condition by which imprinting defects touch more than one locus. Although most cases with MLID present with clinical features characteristic of one imprinting disorder. Imprinting defects also occur in 'molar' pregnancies-which are characterized by highly compromised embryonic development-and in other forms of reproductive compromise presenting clinically as infertility or early pregnancy loss. Pathogenic variants in some of the genes encoding proteins of the subcortical maternal complex (SCMC), a multi-protein complex in the mammalian oocyte, are responsible for a rare subgroup of moles, biparental complete hydatidiform mole (BiCHM), and other adverse reproductive outcomes which have been associated with altered imprinting status of the oocyte, embryo and/or placenta. The finding that defects in a cytoplasmic protein complex could have severe impacts on genomic methylation at critical times in gamete or early embryo development has wider implications beyond these relatively rare disorders. It signifies a potential for adverse maternal physiology, nutrition, or assisted reproduction to cause epigenetic defects at imprinted or other genes. Here, we review key milestones in DNA methylation patterning in the female germline and the embryo focusing on humans. We provide an overview of recent findings regarding DNA methylation deficits causing BiCHM, MLID, and early embryonic arrest. We also summarize identified SCMC mutations with regard to early embryonic arrest, BiCHM, and MLID.

Keywords: DNA methylation; embryo arrest; epigenetics; epimutations; genomic imprinting; infertility; oocyte; subcortical maternal complex.

Figure 1

DNA methylation programming and reprogramming during development in humans and mice. DNA methylation is globally erased in primordial germ cells (PGCs) derived from epiblast during their proliferation and migration to the genital ridges (solid gray line). Therefore, de novo DNA methylation subsequent takes place on a largely blank slate during male and female gametogenesis. In the male, new methylation is established from soon after demethylation and is almost completed by the time of birth (solid blue line). In females, there is no gain of methylation until after birth. Growing oocytes arrested in the first meiosis prophase gain methylation between birth and puberty, as well as in adult life (solid pink line). Maternally and paternally imprinted DMRs become differentially methylated in gametes over the same time window (dashed pink and blue lines, respectively). After fertilization, the parental genomes undergo genome-wide demethylation, which does not include imprinted DMRs (dashed combined pink and blue lines). The timing and extent of demethylation are different for the two parental genomes. The paternal genome is rapidly demethylated in part via TET proteins activity (solid blue line). The maternal genome is protected against TET activity and undergoes passive demethylation following DNA replication (solid pink line). By the time of implantation, the genome–except for imprinted DMRs–undergoes re-methylation events that are necessary for cell-lineage determination (combined red and blue lines). Placenta-specific imprinting that is present only in humans is shown with the solid coral orange line.