Biology Reference
In-Depth Information
cytosine methylation in mammals, allows the exact carbon copy of
methylation patterns from the parental to the newly synthesized strand of
DNA by a maintenance DNA methyltransferase enzyme, DNMT1, and
thus the propagation of DNA methylation patterns to subsequent cell
generations. The intrinsic robustness of this system has been demonstrated
in vitro
, as predetermined states of DNA methylation are conserved over
a hundred cell divisions, provided that the initial methylation density is
high (
Lorincz, Schubeler, Hutchinson, Dickerson, & Groudine, 2002;
Stein, Gruenbaum, Pollack, Razin, & Cedar, 1982
). Because of the truly
epigenetic nature of DNA methylation, this mark is thought to be more
likely to be passed to the next generation upon fertilization and to contribute
to parent-inherited long-term silencing in the progeny, possibly extending
to adulthood. Genomic imprinting is the quintessence of DNA
methylation-based transmission of gametic information occurring in a
parent-of-originmanner with life-long consequences on the next generation
(
Ferguson-Smith, 2011
).
The long-term potential for inheritance of DNA methylation marks has
historically been supported by the lack of DNA demethylase activity, able
to direct the rapid removal of methylated cytosines in mammalian genomes
(
Ooi & Bestor, 2008
). The reversion from methylated to unmethylated states
only seemed possible through passive dilution, requiring multiple cell divi-
sions without replication-coupled maintenance, a mechanism incompatible
with rapid changes in DNA methylation. However, the recent identification
of the ten-eleven translocation (TET) enzymes has provided an avenue by
which demethylation could occur on a short- time scale (
Kriaucionis &
Heintz, 2009; Tahiliani et al., 2009
). TET enzymes catalyze the oxidation
of 5-methylcytosines (5mC) into 5-hydroxymethylcytosines (5hmC), which
could represent an intermediate stage toward unmethylated cytosines (see
Chapter 2
). In direct relevance to the question of gametic inheritance, such
a mechanism permitting active alteration of methylation profiles has been
shown to be potent just after fertilization and to reinforce parental asymmetry
(
Gu et al., 2011; Iqbal, Jin, Pfeifer, & Szabo, 2011; Wossidlo et al., 2011
). This
implies the existence of protective factors, which allow maintenance of
gamete-inherited cytosine methylation at certain loci and the persistence of
genomic imprinting beyond this period.
1.3. Forces exerted to reduce parental epigenetic inheritance
The extent of gametic histone andDNAmodification inheritance is limited by
different forces driving the extensive reprogramming of the early developing
