Life after the Central Dogma
The biotech industry was launched on the scientific myth that organisms
are hardwired in their genes, a myth thoroughly exploded by scientific findings
accumulating since the mid 1970s and especially so since genome sequences have
been accumulating (see Living with the Fluid
Genome, by Mae-Wan Ho ).
We bring you the latest surprises that tell you why our health and
environmental policies based on genetic engineering and genomics are completely
misguided; and more importantly, why the new genetics demands a thoroughly
ISIS Report 07/09/04
Caring Mothers Reduce Response to Stress for Life
How a rat responds to stress depends on whether its mother cared for
it properly as a pup, which marks its genes for life.
Dr. Mae-Wan Ho reports
References for this
article are posted on ISIS members website.
Maternal effects in the spotlight
Maternal effects on the development of offspring are well known. But
they are thought to be due to nutritional and physiological factors affecting
the foetus in the womb; and within the past few years, geneticists have
discovered that diet and stress can profoundly change the pattern of gene
expression in the offspring, affecting their health prospects as adults (see
Diet trumping genes, SiS 20).
A team of researchers from the Douglas Hospital Research Centre and
McGill University in Montreal Canada, and the Molecular Medicine Centre, in
Edinburgh University Western General Hospital in the UK, now report a
remarkable experiment in which the behaviour of the mother nursing her pups not
only affects the pups response to stress as adults, but are correlated
with changes in gene expression states in brain cells that persist into adult
life. Such changes are referred to as epigenetic as they do not
involve alterations in the base sequence of DNA in the genome, only their off
and on states; but they can persist in the brain cells and are passed on to all
the daughter cells.
Caring mothers reduces stress response of pups
In the nest, the mother rat licks and grooms her pups, and while
nursing, arches her back to groom and lick her pups. Some mothers (high
performers) tend to do these more frequently than others (low performers). As
adults, the offspring of high performers are less fearful and show more modest
responses to stress in the hypothalamus-pituitary-adrenal (HPA) neuro-endocrine
Cross-fostering studies showed that the biological offspring of
low-performers reared by high-performers, resemble the offspring of high
performers, and vice versa.
Maternal behaviour, therefore, alters the development of the HPA
responses to stress. The magnitude of the HPA response is a function of the
corticotropin-releasing factor (CRF) secreted by the hypothalamus, which
activates the pituitary-adrenal system. This is modulated by glucocorticoid,
which feeds back to inhibit CRF synthesis and secretion, thus dampening the HPA
responses to stress. The adult offspring of high-versus low performer mothers
show increased glucocorticoid expression the hippocampus, and enhanced
sensitivity to glucocorticoid feedback. If this difference is eliminated, so is
the difference in HPA responses to stress.
Maternal care and gene expression
Previous studies indicate that the maternal behaviour of licking and
grooming and arching her back to do so while nursing increased the expression
of glucocorticoid receptor (GR), accompanied by, among other things, an
increased expression of a special transcription factor, NGF1-A, which binds to
the promoter of the GR gene to increase its transcription and expression. But
how could this be transmitted from the neonate to the adult?
The answer is: through the structure of chromatin (complex of protein
and DNA in the chromosomes), and the methylation of DNA. DNA methylation is a
stable chemical modification of the cytosine in the cytosine-guanine (CpG)
dinucleotides, often associated with stable variations in gene transcription.
Under-methylation of CpG dinucleotides is associated with active transcription.
The researchers decided to look at the methylation state of the GR promoter
around the binding region of the NGF1-A transcription factor in the hippocampus
of adult offspring from high and low performers.
Sure enough, they found highly significant differences in methylation,
with low methylation in offspring from high-performing mothers and high
methylation in offspring from low-performing mothers, corresponding to high and
low expression respectively of the GR.
Cross-fostering results in methylation patterns associated with the
adoptive mother, as consistent with the change in the adult offsprings
responses to stress. Moreover, these epigenetic differences due to maternal
behaviour during the first week of life persisted into adulthood.
A clean slate at birth
Amazingly, the pups of both high and low-performing mothers start out
life genetically the same. Just before birth, the entire region of the GR
promoter was unmethylated in both groups; and day one after birth, methylation
is found in the region in both groups to the same extent.
The changes in methylation pattern then develops within the first week
according to the behaviour of the mother, and thereafter remain for the rest of
their lives. This finding is consistent with earlier studies showing that the
first week of postnatal life is a critical period for the effects
of early experiences on hippocampus GR expression.
The hippocampus is the emotion centre of the brain, and is
believed to be responsible for transferring memory to the rest of the brain. It
is vulnerable to stress and richly supplied with receptors for the sex hormones
Additional markings of the gene
Next, the researchers looked at the structure of chromatin around the GR
gene, as chromatin structure determines whether a gene is transcribed or not.
Chemical modification of the histones (major chromatin protein) by adding an
acetyl- group is a well-established marker for active chromatin
around transcribed genes, which makes it accessible for the transcription
enzyme complex. Again, they found highly significant changes in acetylation
between the two groups of pups. There was greater acetylation and threefold
greater binding of the NGF1-A transcription factor to the GR promoter in the
adult offspring of high- compared with low-performing mothers.
Marked for life?
Now, a critical question is, are these gene-marking changes reversible?
Is the adult doomed to conditioning by the mothers behaviour towards it
as a pup? The general belief is that one is marked for life. DNA methylation
pattern is irreversible. However, recent data from in vitro experiments
suggests that under certain circumstances, it is possible to demethylate DNA by
increasing histone acetylation through a chemical inhibitor of the
deacetylating enzyme, trichostatin A (TSA). The researchers, rather crudely,
infused the adult brain with TSA by applying the solution into the ventricle
(space inside the brain), and obtained more than 3-fold binding of the NGF1-A
protein to the GR promoter in the adult offspring of low-performers, and as
expected, no change in the adult offspring of high-performers. Simultaneously
correlated changes in DNA methylation pattern of the GR promoter was found in
the adults reared by low-performing mothers treated with TSA, but not those
reared by high-performing mothers. In other words, those epigenetic changes
The next question is, are the reversal of epigenetic changes associated
with reversal in HPA responses to stress? The answer, incredibly, is yes. The
TSA treatment, crude as it was, appeared to significantly decreased plasma
corticosterone in the offspring of low-performer in response to stress.
This is all grist to the mill of the fluid and adaptive, adaptable
genome  that makes nonsense of the Central Dogma.