Cell and Molecular Biology of DNA Methyltransferase 1 - International Review of Cell and Molecular Biology - page 22

differentiation inducer was shown to activate Dnmt1 transcription via bind-
ing of Fli-1 to the Dnmt1 promoter in human erythroleukemia cells ( Hodge
et al., 2001 ). Recently, IL6 has been shown to downregulate methylation-
dependent tumor suppressor genes miR-148a and miR-152 ( Braconi et al.,
2010 ). These two microRNAs when are overexpressed result in down-
regulation of Dnmt1 . In CD4 T-cells from systemic lupus erythematosus

patients, miR-126 was found to be upregulated and overexpression of this
micro RNA was inversely correlated with DNMT1 expression ( Zhao et al.,
2011 ). Thus, these three studies suggest that Dnmt1 is regulated post-
transcriptionally by a few microRNAs.
The activity of DNMT1 is associated with diverse biological activities,
including cell proliferation, senescence, and cancer development. The
HMG box-containing protein 1 (HBP1) transcription factor has been iden-
tified as a new repressor of DNMT1 in a complex mechanism during senes-
cence ( Pan et al., 2013 ). HBP1 has multiple lysines that are subjected to
acetylation and differential acetylation has been shown to differently mod-
ulate the expression of DNMT1 and p16. In its hypoacetylated form (with
acetylated K419), HBP1 acts as a transcriptional activator to turn on p16 and
induces senescence, whereas in its acetylated form (with acetylated K171,
K297, K305, K307, and K419), HBP1 acts as a repressor of Dnmt1 by bind-
ing at

þ

134 bp from the transcriptional start site. HBP1-mediated
repression resulted in both gene-specific (e.g., p16INK4) and global DNA
hypomethylation changes.
The genome of placenta is relatively hypomethylated than other somatic
tissues in the embryo ( Monk et al., 1987 ). In placenta, one of the two alleles
of Dnmt1 is silenced with no evidence of imprinting. Silencing of DNMT1
was associated with promoter methylation involving the exon1/intron1
region ( Novakovic et al., 2010 ). However, methylation status of DNMT1
did not affect global 5-methyl-cytosine levels in the extraembryonic tissue.
AUF1 (AU-rich element/poly (U)-binding/degradation factor 1) is a
40-kDa protein that binds to 3 0 -UTR sequences and destabilizes the Dnmt1
transcript ( Torrisani et al., 2007 ). AUF1 levels are regulated in a cell-cycle-stage
dependent degradation by proteasomes. Such AUF1-mediated degradation of
DNMT1 occurs by targeting DNMT1 to the exosome. Because DNMT1's
maintenance methyltransferase function is postreplicative, DNMT1 stabiliza-
tionwas shown tobe achieved throughdegradationof AUF1, specifically in the
S phase of the cell cycle.
In mesenchymal stem cells, Dnmt1 expression is maintained by OCT4 and
NANOG, two transcription factors that are required for maintenance of

115 to