DNA Methylation Patterns During Embryogenesis and Germline Development

Overview of DNA Methylation in Embryogenesis

• DNA methylation patterns are dynamic and undergo significant changes throughout the course of development.
• Key periods of change occur during:
  • Gametogenesis (the formation of gametes).
  • Fertilization.
  • Environmental and developmental transitions.
• The primary goal of these changes is to regulate cell differentiation and the correct establishment of genomic imprinting based on the sex of the developing embryo.

Initial Methylation States and Fertilization

• Prior to fertilization, the two separate gametes possess distinct methylation levels:
  • Sperm: Maintains a relatively high level of methylation, approximately $86\%$.
  • Egg: Maintains a level of methylation that is slightly lower than that of the sperm.
• Upon fertilization, the DNA from both the egg and sperm is combined to form the zygote.

Global Demethylation in the Pre-Implantation Phase

• During the very first week following fertilization, a process of global demethylation occurs.
• The DNA methylation level drops significantly, reaching a low of approximately $43\%$.
• This process involves the loss of a substantial portion of the DNA methylation that was originally contained within the egg and the sperm.
• By the end of this first week, the embryo reaches the stage where it is ready for implantation.

Implantation and Somatic Cell Differentiation

• Following implantation, the cells within the embryo begin to gain methylation marks as they start the process of differentiation.
• By the $3$ to $4$ week mark, basic body patterning is established. This includes:
  • The development of the neural cord.
  • The process of gastrulation.
• Somatic Cells:
  • This category specifically includes gonadal somatic cells and general body somatic cells.
  • As these cells undergo differentiation, they maintain and "hang around" at a fairly high level of DNA methylation.

Germline Development and Imprinting Erasure

• A separate track exists for the pre-germ cells (primordial germ cells), which are destined to become the future eggs or sperm of the individual.
• Once the developmental path for germ cells is decided, a second "huge wave" of demethylation occurs.
• In these specific cells, the methylation level drops extremely low.
• The Erasure of Imprints:
  • This drop is explicitly linked to the erasing of Differentially Methylated Regions (DMRs), also known as imprinting marks.
  • At fertilization, the embryo contains DNA that is half paternal (with paternal imprints) and half maternal (with maternal imprints).
  • Because the individual embryo is either male or female, it cannot pass on a mix of both maternal and paternal imprints to its own future offspring.
  • Consequently, all existing genetic marks must be wiped clean in the cells that will eventually form the gametes.

Re-establishment of Sex-Specific Imprints

• After the period of erasure, the germ cells track along at low methylation levels for a duration before entering the re-establishment phase.
• Sex-Specific Marking:
  • The embryo re-establishes imprints that strictly correspond to its own biological sex.
  • Males: If the baby is male, it puts paternal imprints on all relevant chromosomes. The methylation levels "zoom up" to return the sperm to the roughly $86\%$ level observed in the original male gametes.
  • Females: If the baby is female, it puts female (maternal) imprints on the chromosomes, bringing methylation to the level characteristic of the egg.
• Purpose: This ensures that all chromosomes placed into the individual's gametes are marked correctly (either entirely paternal or entirely maternal) to be passed on to the next generation.