Human Molecular Genetics, Vol 4, 1751-1755, Copyright © 1995 by Oxford University Press
A Razin and R Shemer
Several lines of evidence strongly suggest that DNA methylation is involved
in embryo development. Perhaps the most direct evidence comes from
experiments with methyltransferase deficient mice. Embryos that express low
levels of the maintenance methyltransferase do not develop to term and die
at the 5 to 20 somite stage corresponding to the level of the enzyme. In
the mouse, dramatic methylation changes have been observed during the early
steps of embryo development. Most genes are subject to a process of active
demethylation starting promptly after fertilization. Except for a small
number of methylated CpG sites in imprinted genes the vast majority of the
sites are unmethylated by the stage of cavitation (16 cell). Such
genome-wide demethylation may signify an erasure of epigenetic information
originating in the highly differentiated gametes. This erasure may be
essential for the establishment of a pluripotent state, before specific
cell lineages can be determined. The process of laying down a new
developmental program involves, initially, global de novo methylation at
the stage of pregastrulation followed by gene specific demethylations
associated with the onset of activity of these genes. CpG islands
characteristic of housekeeping genes, appear to be protected from the
global de novo methylation. An exception to this rule is the
hypermethylation of CpG islands in X-linked housekeeping genes on the
inactive X chromosome and of specific differentially methylated CpG sites
in imprinted genes. Primordial germ cells escape the global de novo
methylation which takes place at the pregastrula stage and undergo a very
similar de novo methylation process in the differentiated gonads (15.5-18.5
days post coitum), forming the methylation patterns which are specific to
the gametes. Specific demethylations then form a terminal methylation
pattern which is then clonaly inherited in the soma and erased after
fertilization.
REVIEWS
DNA methylation in early development
Department of Cellular Biochemistry, Hebrew-University Hadassah Medical School, Jerusalem, Israel.
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