Epigenetics in Development
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P136-138
2025-12-17
30
Now that we have discussed how and where epigenetic marks, particularly DNA methylation, exist in the human genome, we will focus on the critical role of epi genetics in human development. Comprehending how these mechanisms function in development will provide a context for their contributions to pathophysiology of certain diseases and disorders. Arguably, one of the most important roles of DNA methylation occurs during embryonic and fetal development, wherein it participates in regulating cell differentiation, conferring a stable cell/ tissue- specific identity. As such, DNA methylation displays tissue- and cell- specific patterns. In fact, tissue of origin is one of the largest determinants of DNA methylation variation in healthy individuals, accounting for greater variation than genetic background.
Epigenetic states are most dynamic during germ cell specification and early embryogenesis, two time periods distinguished by epigenetic reprogramming (Fig. 1). Our knowledge of these processes comes primarily from studies in mice; however, recent genetic and functional data from human studies have shown that epigenetic reprogramming in the gametes and embryo are generally parallel in humans and mouse, although important differences are being identified that require further investigation.
Fig1. The life cycle of imprints. DNA methylation reprogramming during human development. Methylation of imprinting centers (ICs) (dashed black line) is erased more slowly than that of the rest of the genome (black line) in primordial germ cells (PGCs) and reestablished with different kinetics in male (paternal ICs, dashed blue line; whole genome, blue line) and female (maternal ICs, dashed red line; whole genome, red line) germ cells. After fertilization, the maternally and paternally derived genomes are widely demethylated, while differential methylation between maternal and paternal IC alleles (50% level) is maintained preimplantation and postimplantation. Factors and events involved in each stage, 5- methylcytosine level and approximate timing of imprint erasure, establishment and preimplantation and postimplantation maintenance are indicated. gDMRs, Germline differentially methylated regions; GVs, germinal vesicles; SCMC, subcortical maternal complex. (From Monk D, Mackay DJG, Eggermann T, et al: Genomic imprinting disorders: lessons on how genome, epigenome and environment interact, Nat Rev Genet 20:235– 248, 2019. doi:10.1038/ s41576- 018- 0092- 0.)
During primordial germ cell specification in a fetus at ~5 weeks of gestation there is global erasure of DNA methylation followed by remethylation and imprint acquisition in the differentiating germ cells prior to maturing into oocytes or sperm depending on the sex of the fetus. The resulting highly divergent DNA methylation patterns are associated with distinct differentiated/ transcriptional states.
Together, the DNA and histone modifications, as well as molecules that support 3D DNA structure, constitute the epigenome. To that end, after fertilization, the chromatin in the zygote is generally open but not transcribed. This is followed by rapid remodeling leading to zygotic genome activation at the eight- cell stage in human embryos. Prior to implantation the embryo under goes genome- wide DNA methylation reprogramming. This comprises rapid and enzymatically driven/ active demethylation of the paternal genome. By comparison, demethylation of the maternal genome occurs mainly through passive demethylation over several cell divisions. The lowest levels of methylation in the maternal genome occur at the blastocyst stage, at which time the two parental genomes are comparable.
Importantly, the imprinted loci are excluded from this stage of reprogramming, and gametic imprinting marks are retained (see Fig. 1). DNA methylation at these loci is protected from genome- wide demethylation/ remethylation in the embryo. The mechanism, although not yet completely understood, involves protein complexes encoded by maternal effect genes. These genes are transcribed from the maternal genome before fertilization, generating transcripts/ proteins required by the early embryo before zygotic genome activation occurs at the eight- cell stage. The majority of maternal effect genes have been studied in mice, including their phenotypic outcomes when dysregulated by a targeted deletion. Maternal effect genes serve similar functions in humans in that their epigenomic/ organizational role is a requirement for normal developmental competence. See Genomic Imprinting later for phenotypic outcomes associated with pathogenic variants in these genes.
Following implantation, parallel remethylation of the maternal and paternal genomes occurs in a cell- type– dependent and time- dependent manner. Precursor cells (cells that are not yet terminally differentiated) undergo a stepwise differentiation process in which epigenetics plays a critical role. For example, during differentiation, DNA methylation is required to silence pluripotency factors; the promoters of genes associated with pluripotency, such as Oct4 and Nanog, are hypermethylated and silenced. As well, DNA methylation acts to upregulate markers associated with germ- layer specificity. In embryonic stem cells lacking DNA methylation, differentiation is inhibited. While some epigenetic processes are thought to drive transcriptional programs based on various inputs, spatial and temporal, other epigenetic changes are believed to enforce these changes and create a barrier that prevents dedifferentiation. The results of these tightly orchestrated epigenetic patterns are lineage- specific transcription profiles that confer cellular identity. Moreover, these profiles are maintained across cell divisions, as epigenetic patterns are mitotically heritable.
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