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 ecological approach.
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
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.
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 pathway.
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.
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 offspring’s responses to stress. Moreover, these epigenetic differences due to maternal behaviour during the first week of life persisted into adulthood.
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 [2, 3].
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.
Now, a critical question is, are these gene-marking changes reversible? Is the adult doomed to conditioning by the mother’s 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 were reversed.
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 [4] that makes nonsense of the Central Dogma.
Article first published 07/09/04
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