Epigenetics of Reproduction in Animals - Building the Most Complex Structure on Earth - page 71

A noncausal explanation would be that this is a property of living organisms, one
that has evolved in the course of evolution. Such an answer merely circumvents a
legitimate question.
Any causal approach to the problem should start with a close examination of the
proximal causes, i.e., with an understanding of the mechanism of inducing epige-
netic changes in DNA and histones. This approach could show whether any source
of the epigenetic information exists upstream of the DNA and chromatin, and if
this proves to be the case, in a step-by-step approach, to trace back the flow of
the epigenetic information to its ultimate source. If we succeed in going that far
upstream, then we may reveal the causal chain that leads to the production of epi-
genetic structures, which might be the very epigenetic system of heredity we are
looking for.
DNA Methylation/Demethylation
This is the crucial element of gene imprinting, X-chromosome inactivation,
stem cell differentiation, reprogramming, carcinogenesis, chromatin remodeling,
and so on ( Doi et al., 2009; Hewitt et al., 2011 ). DNA methylation is present in
plants and Animalia . It is species-specific, and in multicellulars, it is transmit-
ted to daughter cells. Experimentally induced DNA methylation has sometimes
been transmitted to subsequent generations in multicellulars ( Vandegehuchte
et al., 2010 ).
The methylation of DNA is a function of DNA methyltransferases, which in turn
are activated by extracellular signals; hormones such as glucocorticoids ( Biswas
et al., 1999; Laborie et al., 2003 ), estradiol (E2), ( Lai et al., 2009 ); and by a transcrip-
tion factor (TF), Egr-1 ( Ebert et al., 1994 ). Recall that glucocorticoids produced by
adrenal glands and the E2 produced by gonads are secreted in response to signals from
the pituitary (adrenocorticotropic hormone (ACTH) and follicle-stimulating hormone
(FSH), respectively), that in turn are secreted in response to brain signals, respec-
tively corticotrophin-releasing hormone (CRH) and gonadotropin-releasing hormone
(GnRH). The TF Egr-1 also is regulated cerebrally by the hypothalamic GnRH ( Rachel
Duan et al., 2002 ) and by glucocorticoids ( Loizou et al., 2006 ).
Let us illustrate the role of the nervous system in inducing epigenetic changes
in DNA with two examples. The neural activity resulting from stressful stimuli, via
the protein Gadd45b (growth arrest and DNA-damage-inducible, beta), causes DNA
demethylation in hippocampal and suprachiasmatic nucleus neurons ( Ma et al.,
2009 ). The causal chain from stressful stimuli to DNA demethylation and epigenetic
modification of genes looks as follows:
Stressful stimulus→processing of the stimulus in the stress neurocircuitry→induction of
Gadd45b synthesis→DNA demethylation→expression of neurogenesis genes.
Within 2 h, fear conditioning decreases DNA methylation (hypomethylation) in particular
exons of the bdnf (brain-derived neurotrophic factor) gene in hippocampal neurons of adult
rats ( Lubin et al., 2008 ).