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What role might epigenetics have in shaping a person's development?

2 August 2009
By Professor Marcus Pembrey
Chair, Progress Educational Trust, and Emeritus Professor of Paediatric Genetics, Institute of Child Health, UCL.
Appeared in BioNews 519

Epigenetics is about the when and where of gene activity and about shaping development in response to early experience - from internal cues in the growing embryo to the prevailing physical and the social environment. So it is not surprising that discoveries in epigenetics are being enthusiastically embraced by those who find the fatalism often associated with classical genetics rather soul-destroying. But it is important not to overstate the case for epigenetics. DNA sequence, its variations and mutations remain the backbone of inheritance and evolution.

Nowadays, the term epigenetics refers to the biochemical processes that lead to an enduring change in the pattern of gene activity during development and beyond. It is a form of regulation of gene activity (gene expression) that is not transient and yet does not involve changes in the DNA sequence itself. Epigenetic states influence how the DNA is packaged into the chromosomes - if a gene becomes inaccessible to the molecular machinery that reads the DNA code, it will be silenced. One element in this packaging is DNA methylation – adding methyl groups (CH3) to certain DNA sites. Such epigenetic ‘marks', as they are called, can be faithfully copied during cell division as the organism grows thus explaining the enduring nature of epigenetic states across a lifetime. It has long been recognised (since it became clear nearly all cells carry the complete genome) that some mechanism must exist that results in only the appropriate subset of genes being expressed in any particular cell type or tissue. If this wasn't so, your skin cells would make blood and you would look like a rotting tomato!

So why the recent interest in epigenetics? I think it is the discovery that epigenetic mechanisms can be involved in the developing organism's response to the prevailing environment. The embryo may well be adjusting its growth and developmental trajectory in the light of the intra-uterine environment. So could epigenetics mediate the well established associations between early life circumstances and adult health and character? There are strong correlations between birth weight, for example, and adult onset diseases like coronary heart disease – observations that led to the ‘fetal origins of adult disease' hypothesis. But associations are just that, they don't define the causal pathway. There are several possible explanations; 1) ongoing social patterning – your learnt lifestyle reinforces habits that are good, bad or just different, 2) inherited variations in you or your parents' DNA cause both the early situation and the later outcomes, 3) your early experience alters the pattern of gene actively through epigenetic mechanisms such as methylation of DNA which then persists throughout life, 4) some mechanism(s) that is yet to be discovered. It is likely that all play some part in the correlation of early life exposures with adult outcomes, but evidence is emerging that early experience is more biologically embedded than initially thought. This may well bring comfort, or not of course, to parents regardless of the nature of the child's conception from a genetic point of view.

An elegant series of rat experiments on the effect of parental behaviour on the offspring's adult response to stress show that the enduring effects are down to epigenetic changes at a key gene in the hippocampus, a part of the brain involved in setting the stress response. Using rat strains with different parenting styles, the Canadian team studied the link between the amount of postnatal licking and grooming of the pups and those offspring's level of fearfulness. With less licking during the first postnatal week the offspring grew up more fearful and also tended to show the same parental behaviour, thus perpetuating the fearfulness. Cross fostering pups from one mother type to the other showed that the pups' stress response became that of their adoptive mothers – the trait was not genetically inherited. Subsequently human observations of the epigenetic state of the same gene in the hippocampus were revealing. They studied the brains of suicide victims, some of whom had experienced child abuse and also brains from adults who died from accidents. There was a correlation between the epigenetic state of the relevant gene and child abuse (ref 1, 2). Child abuse is extreme, of course, but even differences in social economic position in early life is associated in the adult with differences in gene expression patterns concerned with the stress response (ref 3). Unfavourable early circumstances were associated with more ‘defensive' patterns of gene activity, as if their blood cells were on ‘Red Alert'. This shift may well turn out to be due to epigenetic modification.

It is early days in epigenetic research and what is true of experimental animals may not always hold true in humans. An important point in terms of triggering an epigenetic modification is likely to be the timing of the experience. Development from egg and sperm formation to completion of puberty is full of critical periods when the organism is more ‘receptive' or ‘vulnerable' to certain influences - depending on your perspective! There is indirect evidence from twin studies that epigenetic variation is already there in the fertilised egg and this raises the big question of whether epigenetic marks acquired in one generation can be passed on by the eggs or sperm. It would be fair to say for humans the jury is still out.

The enduring nature of epigenetic responses to early life experience may not come as a surprise to some people. After all we talk about the ‘formative years'. Nevertheless there are many personal and family issues raised by the emerging research.

References

1 Hyman SE. How adversity gets under the skin. News and Views. Nature Neuroscience 2009; 12:241-3 (This reviews the rat and human research).

2 Child abuse alters expression of stress gene. BioNews 497, 2 March 2009

3 Miller GE et al. Low early-life social class leaves a biological residue manifest by decreased glucocorticoid and increased proinflammatory signalling. PNAS July 14, 2009 (doi:10.1073/pnas.0902971106)

SOURCES & REFERENCES
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