Biology Reference
In-Depth Information
chromatin condensation and accessibility. This is the case specifically for acet-
ylation, which loosens histone and DNA interactions by modifying histone
charge and in turn enhances transcription. In most cases, however, histone
modifications and, in particular, methylation indirectly influence gene expres-
sion through the recruitment of specialized proteins, the histone readers,
which commonly act in association with large chromatin-remodeling
complexes (
Musselman, Lalonde, Cote, & Kutateladze, 2012
). Depending
on the methylation mark and the subsequent binding of different effector
proteins, the impact on transcription can be positive (H3K4 methylation)
or negative (H3K9, H3K27, and H4K20 methylation).
Froma conceptual point of view, histonemodifications are thought to con-
fer a form of flexible regulation. The existence of specialized enzymes, known
as histone modifiers, which catalyze both the establishment and the removal of
histonemarks, is key to allowhighly dynamic patterns of histonemodifications
and, consequently, rapid switches between gene expression programs. This
property enables temporal silencing, poising of developmentally important
genes, and immediate response to signaling pathways (
Bernsteinetal.,2006;
Song, Angel, Howard, & Dean, 2012
). Most importantly, the current lack
of a compelling mechanistic model for mitotic inheritance of histone modifi-
cations has forged the notion that this type of information cannot be autono-
mously propagated in dividing cells and instead requires continuous input from
transcription factors and perhaps, in some cases, from DNA methylation.
The extrapolation of this notion to the context of intergenerational inheritance
has led to the prevailing view that if histone modifications can be passed
from parents to progeny in mammals, they are likely to provide only transient,
short-term information limited to immediate postfertilization stages. None-
theless, the markedly divergent chromatin composition of the oocyte and
sperm, resulting fromdramatically disparate differentiation programs, is amajor
source of parental asymmetry after fertilization.
1.2. Long-term potential of DNA methylation-associated
information
In contrast, DNA methylation is thought to be extremely stable and associ-
ated with long, and sometimes definitive, locked-in silent states. This view
notably emanates from the existence of a faithful and autonomous system of
DNA methylation maintenance, which is intimately coupled to DNA rep-
lication, and has been extensively studied at the biochemical, genetic, and
structural levels (
Bestor & Ingram, 1983; Bostick et al., 2007; Li, Bestor,
& Jaenisch, 1992; Song, Teplova, Ishibe-Murakami, & Patel, 2012
). The
sequence symmetry of CpG motifs, which are predominantly targeted for
