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Epigenetic reprogramming cycle
Preimplantation development
Gametogenesis
Maternal PN
Methylated DNA
Modified histones
Paternal PN
Active DNA demethylation
Hypomodified histones
Gametes
De novo methylation
Passive DNA demethylation
De novo DNA methylation
TE
DNA demethylation
Methylated DNA
Modified histones
ICM
PGCs
Figure 3.5 Epigenetic reprogramming cycle. Epigenetic modifications undergo
reprogramming during the life cycle in two phases: during gametogenesis and preimplantation
development. Primordial germ cells (PGCs) arise from somatic tissue and develop into mature
gametes over an extended period of time. Their genome undergoes DNA demethylation in the
embryo between E11.5 and E12.5, including at imprinted genes. Following demethylation, the
genomes of the gametes are de novo methylated and acquire imprints; this process continues
up to E18.5 in males and in maturing oocytes before ovulation in females. Fertilization
signals the second round of reprogramming during preimplantation development. The paternal
genome is actively demethylated, and its histones initially lack some modifications present in
the maternal pronucleus (PN). The embryo's genome is passively DNA-demethylated during
early cell cycles before blastulation. Despite this methylation loss, imprinted genes maintain
their methylation through this preimplantation reprogramming. De novo methylation roughly
coincides with the differentiation of the first two lineages of the blastocyst stage, and the
inner cell mass (ICM) is hypermethylated in comparison to the trophectoderm (TE). These
early lineages set up the DNA methylation status of their somatic and placental derivatives.
Histone modifications may also reflect this DNA methylation asymmetry. Particular classes of
sequences may not conform to the general genomic pattern of reprogramming shown here.
Source : From Morgan et al., 2005 .
Santos et al., 2002 ). An enzyme called Tet3 oxidase may be responsible for this
demethylation. Demethylation of the paternal genome is independent of the DNA
replication and represents a general feature of fertilization in almost all examined
mammals ( Lepikhov et al., 2008 ). Before the first cleavage division in the male
genome, processes of histone modification also occur.
In contrast to this early dynamic behavior of the male pronucleus, the processes
of the DNA demethylation and histone modification/chromatin remodeling in the
female genome are delayed. Demethylation of the egg DNA after fertilization is a
passive process determined by the lack of methylation enzymes during the replica-
tion of the egg DNA ( Figure 3.5 ). Imprinting of parental genes is protected against
this epigenetic reprogramming of the genome ( Morgan et al., 2005 ).
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