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Free keywords:
bivalent domains, NSC, genomic imprinting, transposons, molecular clocks, early life stress, Avp, polycomb
Abstract:
Epigenetic mechanisms encode information above and beyond DNA sequence
and play a critical role in brain development and the long-lived effects
of environmental cues on the pre- and postnatal brain. Switch like,
rather than graded changes, illustrate par excellence how epigenetic
events perpetuate altered activity states in the absence of the initial
cue. They occur from early neural development to maturation and can give
rise to distinct diseases upon deregulation. Many neurodevelopmental
genes harbor bivalently marked chromatin domains, states of balanced
inhibition, which guide dynamic "ON or OFF" decisions once the balance
is tilted in response to developmental or environmental cues. Examples
discussed in this review include neuronal differentiation of embryonic
stem cells (ESC) into progenitors and beyond, activation of Kiss1 at
puberty onset, and early experience dependent programming of Avp, a
major stress gene. At the genome-scale, genomic imprinting can be
epigenetically switched on or off at select genes in a tightly
controlled temporospatial manner and provides a versatile mechanism for
dosage regulation of genes with important roles in stem cell quiescence
or differentiation. Moreover, retrotransposition in neural progenitors
provides an intriguing example of an epigenetic-like switch, which is
stimulated by bivalently marked neurodevelopmental genes and possibly
results in increased genomic flexibility regarding unprecedented
challenge. Overall, we propose that molecular epigenetic switches
illuminate the catalyzing function of epigenetic mechanisms in guiding
dynamic changes in gene expression underpinning robust transitions in
cellular and organismal phenotypes as well as in the mediation between
dynamically changing environments and the static genetic blueprint.