Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 24

linked cluster of genes. Each DMD is relatively small, averaging approxi-
mately 4 kb.
In the first few cell cycles of embryogensis, during preimplantation
development, DNMT1 is expressed in the nuclei of different cleavage stages.
Two forms of DNMT1, DNMT1s and DNMT1o play essential roles in
maintenance methylation of the imprinted DMDs. As a result, loss of
DNMT1s results in failure of maintenance methylation for these domains
in all divisions of preimplantation, except the 8-cell stage where there is a
loss of nuclear DNMT1o but not nuclear DNMT1 ( Cirio et al., 2008a ).
The role of DNA methylation on imprinting was also studied using two
mutant Dnmt1 alleles, Dnmt1 c and Dnmt1 n , which are null and hypomorphic
alleles, respectively ( Weaver et al., 2010 ). A majority of imprinted genes had
altered expression (equivalent expression of both parental alleles) in a homo-
zygous Dnmt1 c/c mutant background, whereas the degree of alteration of
imprinting varied for different imprinted genes in a homozygous Dnmt1 n/n
mutant background. For instance, Cdkn1c imprinting is unaffected in
Dnmt1 n/n embryos but affected in Dnmt1 c/c embryos. Igf2- and Peg3 -
imprinted domains on the other hand demonstrated biallelic expression in
both Dnmt1 n/n and Dnmt1 c/c backgrounds. Imprinting of Kcnq1ot1 showed
complex patterns of expression in embryos and placenta with the two
genetic backgrounds. In Dnmt1 n/n animals, Kcnq1ot1 expression was biallelic
in embryos but imprinting was unaffected in the placenta, whereas both
embryos and placenta had loss of imprinting in Dnmt1 c/c background. These
results suggest that the altered levels of DNMT1 activity can impact main-
tenance of monoallelic expression of certain imprinted genes depending on
the tissue type.
Recent results suggest a mechanism by which noncoding RNAs through
interaction with DNMT1 play a role in maintenance methylation of
imprinted genes. For instance, the imprinted Kcnqot1 gene, which expresses
a noncoding RNA, regulates both ubiquitous and tissue-specific imprinting
of the Kcnq1 cluster of imprinted genes. The silencing domain of the
ncRNA is 890 bp long, located 610 bp downstream to the transcription start
site. Maternal deletion of the 890 bp did not affect imprinting, whereas
paternal deletion resulted in biallelic, nonimprinted expression of normally
imprinted genes to variable extents and in tissue-specific manners. The dele-
tion also affected methylation of somatically acquired DMDs. Wild-type
Kcnqot1 noncoding RNA had been shown to interact and recruit DNMT1
to these DMDs and this interaction is very much reduced in mice with dele-
tion of this 890-bp region ( Mohammad et al., 2010 ).