Epigenetic Reprogramming in Mice and Humans: From Fertilization to Primordial Germ Cell Development

Abstract

In this review, advances in the understanding of epigenetic reprogramming from fertilization to the development of primordial germline cells in a mouse and human embryo are discussed. To gain insights into the molecular underpinnings of various diseases, it is essential to comprehend the intricate interplay between genetic, epigenetic, and environmental factors during cellular reprogramming and embryonic differentiation. An increasing range of diseases, including cancer and developmental disorders, have been linked to alterations in DNA methylation and histone modifications. Global epigenetic reprogramming occurs in mammals at two stages: post-fertilization and during the development of primordial germ cells (PGC). Epigenetic reprogramming after fertilization involves rapid demethylation of the paternal genome mediated through active and passive DNA demethylation, and gradual demethylation in the maternal genome through passive DNA demethylation. The de novo DNA methyltransferase enzymes, Dnmt3a and Dnmt3b, restore DNA methylation beginning from the blastocyst stage until the formation of the gastrula, and DNA maintenance methyltransferase, Dnmt1, maintains methylation in the somatic cells. The PGC undergo a second round of global demethylation after allocation during the formative pluripotent stage before gastrulation, where the imprints and the methylation marks on the transposable elements known as retrotransposons, including long interspersed nuclear elements (LINE-1) and intracisternal A-particle (IAP) elements are demethylated as well. Finally, DNA methylation is restored in the PGC at the implantation stage including sex-specific imprints corresponding to the sex of the embryo. This review introduces a novel perspective by uncovering how toxicants and stress stimuli impact the critical period of allocation during formative pluripotency, potentially influencing both the quantity and quality of PGCs. Furthermore, the comprehensive comparison of epigenetic events between mice and humans breaks new ground, empowering researchers to make informed decisions regarding the suitability of mouse models for their experiments.

Keywords: developmental toxicity; embryo development; epigenetic reprogramming.

Figure 1

DNA methylation levels during mouse and human embryo development from fertilization to PGC development. The methylation levels of the CpG islands are shown in the figure. The sperm genome is highly methylated (~75–80%), and the oocytes are relatively less methylated (~50%). After fertilization, global demethylation mediated by Tet enzymes occurs in the parental genomes, dropping the methylation to ~20% at the blastocyst stage. The process is rapid in the paternal genome and gradual in the maternal genome. The ICR remain methylated during this demethylation. The methylation is then restored gradually from the blastocyst stage to the gastrula stage by Dnmt3a and Dnmt3b enzymes. The inner cell mass (ICM) in the blastocyst is in naïve pluripotent stage, the epiblast comprises formative pluripotent state and beginning of gastrulation is primed pluripotency state before the cells divide into endoderm, mesoderm, and ectoderm by the end of gastrulation. PGCs first appear at E5.5 in the formative pluripotent stage and become prominent by E6.5. Dnmt1 maintains the DNA methylation levels in somatic cells. The second round of global demethylation occurs again in the PGC by the action of Tet enzymes. The PGCs have the least methylated genome in the entire lifespan of the mice as the parent-of-origin imprints are erased (~3–4%) [10] and new ones are established. The methylation of the sperm gradually increases by the action of Dnmt3a and Dnmt3b and is restored before birth. However, in oocytes, the methylation remains low and is restored at puberty. The timings for epigenetic events for both mice and humans are shown at the bottom of the figure.