Biology Reference
In-Depth Information
This suggests that TET enzymes have a locus-specific role in demethylation
in PGCs or that TET2 compensates for the absence of TET1, which needs
to be further investigated. One might also predict that TET2 is involved in
DNA demethylation during hematopoietic differentiation, but this has also
not been studied.
What are the possible mechanisms for TET-mediated DNA demethyla-
tion? One scenario is that the oxidation derivatives lead to passive demethyl-
ation upon DNA replication (
Fig. 2.6
). This is supported by the observation
that 5hmC, 5fC, and 5caC signals in preimplantation embryos persist in the
cleavage-stage embryos and are gradually diluted with each cell division
(
Inoue & Zhang, 2011; Inoue et al., 2011
). In addition, it has also been shown
that DNMT1 is not active on hemihydroxymethylated DNA (
Hashimoto
et al., 2012
). Alternatively, TET-mediated oxidation of 5mC could lead to
NH
2
CH
3
N
5mC
AID/APOBECs
N
O
TETs
OH
NH
2
OH
NH
2
O
NH
2
O
C
O
O
CH
3
CH
2
CH
2
OH
CH
N
N
N
N
N
T
5hmU
5hmC
5fC
5caC
AID
APOBECs
TETs
TETs
N
N
N
N
O
O
O
O
N
O
Replication or TDG/SMUG1, BER
NH
2
TDG/SMUG1, BER
Deformylase?
N
TDG/MBD4, BER
Decarboxylase?
C
N
O
Figure 2.6 Potential chemical pathways for active cytosine demethylation. One poten-
tial mechanism for active replication-independent demethylation is deamination of
5mC into thymine (T) by cytosine deaminases AID or APOBEC, followed by excision
of the thymine by DNA glycosylases TDG or MBD4 and base excision repair (BER).
5mC can also be converted into 5hmC by TET enzymes, which can further be oxidized
into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), or deaminated into 5-
hydroxymethyluracil (5hmU). All these modified bases could lead to replication-
dependent passive demethylation or active demethylation via excision by DNA
glycosylases (TDG, SMUG1) followed by BER. In addition, a putative decarboxylase or
deformylase could convert 5caC or 5fC directly back to cytosine, but such enzymes have
not yet been discovered.
