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and observed that TET1 binds preferentially to CpG-rich regions in
promoters and within genes, possibly owing to the presence of the CXXC
domain ( Williams et al., 2011; Wu, D'Alessio, Ito, Xia, et al., 2011; Xu
et al., 2011 ). From this data, it has been proposed that TET1 could contribute
to maintain CpG islands in a hypomethylated state by counteracting spuri-
ous de novo CpG methylation ( Branco, Ficz, & Reik, 2011; Williams,
Christensen, & Helin, 2012 ). Yet the exact role of TET1 in ES cells is still
debated as several groups reported that TET1 depletion leads to down-
regulation of pluripotency factors and loss of stem-cell identity ( Ficz et al.,
2011; Freudenberg et al., 2012; Ito et al., 2010 ), whereas others did not
see major effects on ES cell self-renewal and pluripotency ( Dawlaty et al.,
2011; Koh et al., 2011; Williams et al., 2011 ). Another layer of complexity
comes from the observation that TET1-bound genes can be both active
and inactive, and that downregulation of TET1 in ES cells leads to transcrip-
tional upregulation and downregulation ( Ficz et al., 2011; Williams et al.,
2011; Wu, D'Alessio, Ito, Xia, et al., 2011; Xu et al., 2011 ). This suggests that
TET1 plays multiple roles in gene regulation, some of which is potentially
independent of its catalytic activity ( Williams et al., 2011 ).
Knockouts for the Tet genes have now been generated in mice. Surpris-
ingly, Tet1 -null mice are viable ( Dawlaty et al., 2011 ), indicating that the
defects observed in TET1-deficient ES cells do not translate into develop-
mental failure in vivo . Nevertheless, Tet1 / mice display a smaller body
size at birth, which might reflect a developmental delay. Tet1 / mice
are also subfertile, which revealed that TET1 is crucial for the progression
through meiosis ( Yamaguchi et al., 2012 ). TET2 plays key roles in
hematopoiesis, as first evidenced by the discovery that TET2 mutations
are frequent in human myeloid malignancies such as myeloproliferative
neoplasms, chronic myelomonocitic leukemia (CMML), myelodisplastic
syndrome, and AML ( Abdel-Wahab et al., 2009; Delhommeau et al.,
2009; Langemeijer et al., 2009 ), as well as in B- and T-cell lymphomas
( Quivoron et al., 2011 ). Consistent with TET2 being a key regulator of
hematopoiesis, Tet2 knockout in mice does not affect embryonic develop-
ment but leads to severe hematopoietic defects ( Ko et al., 2011; Li et al.,
2011; Moran-Crusio et al., 2011; Quivoron et al., 2011 ). Mice first show
an enlargement of the hematopoietic progenitor cell pool and an increased
self-renewal capacity of hematopoietic stem cells, which ultimately leads to
CMML-like myeloid malignancies at 4-6 months of age and death. Finally,
TET3 is highly expressed in oocytes and has been implicated in epigenetic
reprogramming in the zygote. Embryos derived from Tet3 -deficient oocytes
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