Functions of DNA Methylation and Hydroxymethylation in Mammalian Development - Current Topics in Developmental Biology - page 51

when it is trimethylated ( Dhayalan et al., 2010 ), suggesting that DNA meth-
ylation might be guided to chromatin carrying the H3K36me3 mark. This is
compatible with the observation that DNA methylation and H3K36me3
overlap in mammalian cells, in particular, in the body of genes ( Ball
et al., 2009; Blackledge et al., 2010; Kolasinska-Zwierz et al., 2009 ).
DNMT3A, DNMT3B, and DNMT3L also possess a cysteine-rich ADD
(ATRX-DNMT3-DNMT3L) domain ( Fig. 2.2 A) with affinity to histone
H3 when it is unmethylated on lysine 4 ( Ooi et al., 2007; Otani et al.,
2009; Zhang, Jurkowska, et al., 2010 ). This suggests that the presence of
H3K4 methylation prevents the recruitment of DNMT3 enzymes to chroma-
tin, which provides one possible mechanism for the strong anticorrelation
betweenDNAmethylation andH3K4methylation observed in genome-wide
studies ( Meissner et al., 2008; Weber et al., 2007 ).
2.2. Proteins of the TET family
The TET proteins TET1-3 are 2-oxoglutarate and Fe(II)-dependent
dioxygenases that convert 5mC into 5hmC using a -ketoglutarate as a
cosubstrate ( Itoetal.,2010;Tahilianietal.,2009 ). The founding member
TET1 was initially identified as a fusion partner of MLL in acute myeloid leu-
kemia (AML) ( Lorsbach et al., 2003; Ono et al., 2002 ). TET proteins can also
further oxidize 5mC into 5-formylcytosine (5fC) and 5-carboxylcytosine
(5caC), which is probably of physiological importance because 5fC and
5caC are detectable in DNA from ES cells and early embryos ( He et al.,
2011; Inoue, Shen, Dai, He, & Zhang, 2011; Ito et al., 2011 ). The TET pro-
teins share a conserved catalytic domain composed of a double-stranded
b -helix (DSBH) region downstream of a cysteine-rich domain ( Fig. 2.2 B).
Another characteristic of the TET proteins is that TET1 and TET3 contain
a CXXC domain in their N-terminus ( Fig. 2.2 B). Unlike the CXXC
domains in DNMT1, MLL, MBD1, or CFP1 that bind unmethylated CpGs,
the function of the TET1 CXXC domain is less clear. Some studies showed
that the human TET1 CXXC domain binds methylated and unmethylated
CpG-rich DNA ( Xu et al., 2011; Zhang, Zhang, et al., 2010 ), whereas
another study reported that the mouse TET1 CXXC has no DNA-binding
activity ( Frauer et al., 2011 ). The three TET proteins have distinct expression
patterns, suggesting possible nonoverlapping functions. TET1 and TET2 are
highly expressed in ES cells, TET2 is also abundant in hematopoietic cells, and
TET3 is present in oocytes. As TET1 is abundant in ES cells, this protein has
been the most studied so far. Several groups performed ChIP-Seq in ES cells