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levels and detailed features of genomic CpG methylation are highly depen-
dent on the specific stage in the cycle ( Smith et al., 2012 ). Most notably, the
lowest level of genomic methylation in primordial germ cells is very signif-
icantly less than the maximum level found in adult somatic cells ( Monk et al.,
1987; Smith et al., 2012 ).
As we shall see in the following discussions, examining DNA methyla-
tion in mammalian species during the entire life cycle, rather than in the
narrow confines of a single-cell division in a specific cell type, reveals the
possibility that maintenance methylation is likely to be a highly regulated
phenomena. In turn, elucidating the functions of DNMT1 over this
extended time frame may provide insight into its molecular function in
any given cell type at any given developmental time.
4.2. Developmental patterns require de novo methylation,
maintenance methylation, and demethylation
There are three basic activities that underlie changes in genomic methylation
during development. DNA methylation states must be dynamically regu-
lated by de novo methylation and demethylation events, and also maintained
for extended periods while cells are proliferating and DNA is replicating.
Generically, the increases in methylation are due to de novo methylation pro-
cesses and the decreases are due to demethylation processes. Prototypes of
demethylation and de novo methylation are from A. thaliana (described in
Sections 5 and 6 , respectively), and this information has been used to gain
insight into mechanisms of the comparable required activities in mammals.
In this section, we will discuss maintenance methylation, which is important
because there are also periods in the life of a mammal in which cells divide,
yet there is little if any remodeling of genomic DNA methylation patterns.
The enduring expression of DNMT1 in the face of decreases and increases in
genomic methylation (both decreases and increases sometimes occurring
simultaneously, but on different genomic sequences) raises the possibility
that DNMT1 is directly or indirectly involved in these functions. Impor-
tantly, maintenance methylation appears to be largely independent of de novo
methylation and demethylation. The requirement for maintenance methyl-
ation can be addressed in experiments in which adverse consequences of
mutations in genes encoding maintenance methyltransferases are observed.
4.3. Regulation of Dnmt1 expression
There are very likely to be many ways in which Dnmt1 expression is con-
trolled. A few pertinent examples are discussed in this section. IL6, a
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