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illegitimate recombination ( Bourc'his & Bestor, 2004; De La Fuente et al.,
2006 ). The role of DNA methylation in suppressing mobile elements is also
evident in plants and fungi, which had led to speculate that DNA methyl-
ation may have primarily evolved for the purpose of repressing mobile ele-
ments. This view is, however, challenged by recent data showing that
repeats are not methylated in many invertebrate species like the honey
bee, silkworm, ants, or sea squirts ( Bonasio et al., 2012; Feng et al., 2010;
Lyko et al., 2010; Xiang et al., 2010; Zemach, McDaniel, Silva, &
Zilberman, 2010 ).
5. EMERGING FUNCTIONS OF CYTOSINE
HYDROXYMETHYLATION
5.1. Role in DNA methylation erasure
The discovery of the catalytic properties of TET proteins led to the hypoth-
esis that TET-mediated 5mC oxidation could initiate DNA demethylation,
both by passive and by active mechanisms. This has been well documented
in the context of postfertilization reprogramming. Using specific antibodies
against the diverse form of modified cytosines, immunofluorescence studies
have revealed that the loss of 5mC signal in the zygote on the paternal
genome coincides with the appearance of 5hmC ( Iqbal, Jin, Pfeifer, &
Szabo, 2011; Wossidlo et al., 2011 ), as well as 5fC and 5caC ( Inoue
et al., 2011 ; Fig. 2.4 ). The appearance of 5hmC in the paternal pronucleus
is also observed in bovine and rabbit zygotes, which suggests an evolutionary
conserved process ( Wossidlo et al., 2011 ). In addition, inactivation of TET3
in the zygote by conditional knockout or RNAi impairs the formation of
5hmC and the erasure of DNA methylation measured by immunofluores-
cence and bisulfite sequencing at LINE1 transposons and genes Oct4 , Nanog ,
and Lemd1 ( Gu et al., 2011; Wossidlo et al., 2011 ). This is associated with
developmental failures in the embryo, probably due to the persistent DNA
methylation that interferes with the activation of early embryonic genes ( Gu
et al., 2011 ). Altogether, this reveals a pathway in which TET-mediated
conversion of 5mC to 5hmC initiates DNA methylation erasure in preim-
plantation embryos. TET1 and TET2 are also expressed in PGCs and TET-
mediated oxidation occurs in PGCs at the time of global demethylation
( Hackett et al., 2013 ). However, the TET1 knock-out in mice revealed that
TET1 is not essential for the genome-wide demethylation in PGCs but par-
ticipates in the demethylation of meiotic genes ( Yamaguchi et al., 2012 ).
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