Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 23

pluripotency. Downregulation of Oct4 and Nanog results in repression of
Dnmt1 and derepression of genes associated with development and lineage
differentiation including p16 and p21 ( Tsai et al., 2012 ). From this data,
DNMT1 appears to help inmaintenance of mesenchymal stem cell properties.
Dnmt1 is frequently overexpressed in cancers and the mechanisms of this
overexpression are quite varied. Several transcription factors such as sp1/sp3,
E2F, and STAT3 have been shown to regulate the expression of Dnmt1
( Kimura et al., 2003; Kishikawa et al., 2002; Zhang et al., 2006 ). Interest-
ingly, Dnmt1 expression can involve a crosstalk between estrogen-related
receptor g (ERR g ) and SHP (small heterodimer partner), a unique member
of nuclear receptor superfamily ( Zhang and Wang, 2011 ). In this case, SHP
has been shown to interfere with activation of Dnmt1 promoter by ERR g .
Recently, metal-responsive transcription factor-1 (MTF-1), which is
expressed in the presence of zinc, has been shown to induce Dnmt1 pro-
moter by repression of SHP, effectively a negative regulator of Dnmt1
( Zhang et al., 2012a ). Thus Dnmt1 expression can be induced by zinc
and this expression is medicated through an antagonism between MTF-1
and SHP.

4.4. DNMT1 s role in imprinting

As shown in Fig. 1.7 , methylation on certain DNA sequences associated
with imprinted genes is inherited or maintained following fertilization. As
mentioned above, this form of epigenetic inheritance is highly dependent
on protein products of the Dnmt1 maintenance methyltransferase gene
and offers solid support for DNMT1's role in maintaining methylation pat-
terns after DNA replication. Here, we will discuss various genetic experi-
ments, primarily ones involving the generation and study of different
mutant alleles of the mouse Dnmt1 gene, which provide strong support
for roles of the Dnmt1 gene in the inheritance of genomic imprints.
Genomic imprints are established in male and female germ cells as dense
patterns of CpG methylation on differentially methylated domain (DMD)
sequences ( Reinhart and Chaillet, 2005 ). One parental allele of a particular
DMD sequence is highly methylated and the opposite allele is unmethylated.
After fertilization, or fusion of the two gametes with distinct DMD sequence
methylation, DMD methylation states are inherited. That is, the
unmethylated allele maintains its unmethylated state and the methylated
allele maintains its methylation. There are approximately 16 DMD regions
in the mouse genome, and each DMD governs the imprinting of a tightly

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