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The basics of epigenetics.

At one time scientists described DNA as fate. Now they know that DNA is potential, because experience—principally early life experience—plays a big part in how genes behave. The experience we’re talking about ranges from how your parents lived before you were conceived to how your mother felt and what she ate during pregnancy, and aspects of your early life such as how your parents treated you in your early months, what you ate, whether people spoke to you and allowed you to explore.

So it seems that experience and exposure hold the potential to influence the way genes play their part in foetal development and in life as an independent individual. “It is not simply the presence of genes”, Professor Frances Champagne, Associate Professor of Psychology, Columbia University in New York City, wrote in her landmark article “Epigenetic Mechanisms and the Transgenerational Effects of Maternal Care”, “but rather levels of gene expression that led to individual variations in offspring characteristics”.

EPIGENETICS AND GENE EXPRESSION
To understand the notion of gene expression, start with genes. Genes embody codes for cell behaviour, but genes themselves are passive. A cast of other chemical players transcribe, format and transmit code into proteins and on into body structures and behaviour observable up the line.

In order to transcribe the code, first-line players need access to the genes—which they may or may not get depending in large part on events in one’s life. And that’s where experience comes into the picture. The nature of experience—what you ingest, what you do, what others do—determines in large part how well those agents are able to play their parts in executing the genetic code—or, as scientists describe it, in gene expression.

Study about the impact of experience on gene expression is epigenetics. Here’s a very high-level look at two mechan-isms that are central to the silencing or expression of genes.

METHYLATION AND ACETYLATION
Genetic material is organised as chromatin, which is segments of double-helix DNA wrapped around clusters of a protein called histone. The wrapped clusters may be grouped tightly together, keeping the agents out (not allowing for transcription), or opened out and available to the various chemical players who transcribe a gene’s code, make proteins, build cells and otherwise get the process of development and reacting underway.

Histone Acetylation
Whether the chromatin strands open out depends largely on the action of acetyl groups. Acetyl groups attach to, and remove the positive charge from, histones. The effect is to decrease interaction with the negatively charged DNA. That allows a more relaxed chromatin complex which opens the way for the next line of actors to file in and activate the appropriate genes. Acetylation is intermittent and reversible as events, and one’s experience of events, flow.

Cytosine Methylation
Sometimes methyl groups attach to the DNA’s cytosine component. This has the effect of blocking the attachment of proteins that turn the gene on, effectively silencing the gene. Thus the gene’s code will not be copied or translated into a structure or function in the body. And with exceptions, silencing by methylation seems to be permanent (although there are demetylation enzymes, and it is not only through genome-wide reprogramming that they are used).

Since every cell contains the full genetic complement, methylation is essential to development. That is, the gene coding for heart cell is active when the cell is destined for the heart, and the genes in that cell for making all the other tissue types are silenced by methylation. But as you can imagine, this silencing can be very harmful if it silences genes that promote normal development and good health.

To illustrate we describe studies by two prominent biomedical scientists working in the field of epigenetics.

HOW EARLY LIFE EXPERIENCE INFLUENCES GENE EXPRESSION
Professor Frances Champagne has led the way in explaining two compelling issues: how painful experience creates undesirable DNA behaviour—which in turn causes risk to health and well-being—and the possibilities for mitigating those effects.

At the Champagne Lab, research examines develop-mental plasticity in response to environmental exper-iences. The research team are particularly interested in the impact of early life experiences on behaviour, the neural mechanisms associated with these environmentally mediated effects and the epigenetic changes that allow these effects to persist within and across generations.

“Epigenetic Programming by Maternal Behaviour,” published in 2004 with co-authors, reported that maternal nurturing among rats produced fixed chemical modification of offspring DNA. The report elucidated the mechanisms underlying the transmission as well.

Specifically, investigators found that licking, grooming and arched-back nursing positively influenced the glucocorticoid receptor (GR) gene promoter in the hippocampus, which in turn enhanced the individual’s ability to manage stress. This works in a negative feedback loop: the more glucocorticoid receptors the more cortisol signals shutting down the stress response more quickly.

Furthermore, where offspring nurturing was modest or low, investigators noted the opposite GR effect: fewer GR receptors in the hippocampus, less cortisol sending signals, longer high-stress reaction.

The team hypothesised that fostering pups to high-nurturing mothers would reverse negative epigenetic effects and improve the individual’s ability to handle stress; that proved true, and furthermore the altered effects endured into the pup’s adult life.

Professor Champagne and colleagues demonstrated that a gene is fixed but its expression may be influenced by experience—and with this report, the field of epigenetics came into its own.

In “Epigenetic Mechanisms and the Transgenerational Effects of Maternal Care”, a milestone review paper, Professor Champagne characterised maternal behaviour and looked for associations with offspring development. She confirmed results of earlier studies showing that the degree of licking and grooming a female pup experiences is replicated in the pup’s own maternal behaviour—and further, showed that this maternal care pattern can continue across many generations.

In this paper she reported that the neuro-biochemical steps leading to transmission of behaviour were not, as some scientists thought, the result of an environmentally-induced gene mutation; rather the pathways proceeded via estrogen-oxytocin interactions and the differential methylation of hypothalamic estrogen receptors. The results state further that the mechanisms were probably connected with methylation patterns of the gene that codes for estrogen receptors.

In addition to this work, Dr Champagne has studied the neurobiological consequences of prenatal stress, maternal separation and/or deprivation, juvenile social environment and adult social stress, and she has written about epigenetic disruption following neonatal exposure to BPA.

EPIGENETICS, REPROGRAMMING AND THE WORK OF WOLF REIK
The effect of chemical tags on the behaviour of genetic material—and ultimately on observable structures and behaviour—is called epigenetics. The reaction to stress in early life is just one among thousands of epigenetic events. Each individual develops his or her own epigenetic profile and children inherit some of the tags.

What effect do those tags have on choices we make, reactions to events, mental health and other aspects of development? Can we erase the undesirable ones resulting from inflammation, stress and events beyond our control such as early rearing patterns?

Wolf Reik, a prominent cell biologist at the UK’s Babraham Institute in Cambridge, is committed to under-standing these processes and their effect on inheritance, development and health.

Reprogramming
As a new individual develops from the union of sperm and egg, the parents’ epigenetic tags are wiped almost clean, leaving the DNA virtually unmethylated, ready to document its own experience history.

The return of a cell to an unmethylated state is called epigenetic reprogramming. How parental marks are erased, when and why this happens, how the marks that do remain affect the genetic material and the developing individual—those and more are questions that Professor Reik studies, principally though not exclusively using mice.

Where Reprogramming Takes Place
Natural epigenetic reprogramming occurs on a genome-wide scale both in precursors of mature germ cells, the primordial germ cells (PGCs), and in the zygote shortly after fertilisation. Both histone marks (acetylation) and DNA methylation are reprogrammed, and the erasure of epigenetic information is substantial.

This seems to limit the extent to which acquired epi-genetic information can be transmitted from one generation to the next. This epigenetic reprogramming of germ cells is an essential characteristic of their immortality and occurs in preparation of its acquisition of totipotency, the ability of a single cell to divide and produce all of the differentiated cells in an organism. However, defects in erasure of epigenetic information occur, and this may lead to transgenerational epigenetic inheritance.

Epigenetic programming also occurs on embryonic stem (ES) cells, and Dr Reik has carried out one of the first genome-wide mapping study of hydroxymethylation in ES cells, which has revealed continuous reprogramming of methylation patterns in these pluripotent cells—those that can differentiate into any of the three main types of somatic cell—which is likely associated with their plasticity. Scientists at Dr Reik’s lab have recently discovered that embryonic stem cell signalling regulates genome-wide epigenetic reprogramming—partly by controlling methylases and demethylases.

Dr Reik looked at plant genetics—perhaps because they have no recourse to behavioural responses in coping with stressful environments, plants appear to have honed genetic and epigenetic strategies for adaptation 17to a much greater extent than animals—which also undergo demethylation, and found mammalian enzymes very similar to those which are responsible for plant demethylation. He found that the protein AID is at least partially responsible for erasing epigenetic tags in mammal primordial germ and embryonic cells and is continuing work to unravel the complex web of enzymes responsible for this important step in our species growth and stability.

For this study, mouse tissues, including male and female PGCs at E13.5, were isolated from C57BL/6J mice, C57BL/6J mice transgenic for Oct4-Gfp, or Aid-/- knockout mice bred into a C57BL/6J background for seven generations prior to this study.

Recently Dr Reik’s lab initiated work on epigenetic regulation of social behaviour in insects. He and his team are interested in how DNA methylation in the brain is linked with the evolution of sociality.

Dr Reik’s interest in genetic reprogramming also includes work with induced pluripotent stem cells (iPS) which are somatic cells reprogrammed to be pluripotent and therefore available to become any cell type. Some research in his lab focuses on transposons, which are segments of DNA that literally cut-and-paste, inserting themselves into adjacent or other places on the helix. These transposable genetic elements (transposons and retrotransposons) constitute more than half the DNA in higher eukaryotes. Most transposable elements appear to be silenced: how and why are questions left to be answered.

CAN YOU INFLUENCE THE BEHAVIOUR OF YOUR GENES?
Thanks to Frances Champagne, Wolf Reik and their colleagues, we have sophisticated information about how and under what circumstances early influence shapes later life outcomes and about how epigenetic marks in germ cells are erased and reset to ensure normal development. They helped to establish that proper DNA methylation, histone methylation and histone acetylation—in germ cells and in fully mature offspring—are essential to a healthy and happy life. In the first instance nature holds the reins; in the second, it is up to us to choose.

ADDITIONAL READING

Helen Kelly is an ALN World Contributing Editor reporting on news in biomedical science, health and management worldwide. HelenKellyLtd@aol.com

Laura E. Kelly L.Ac is a Primary Care Physician in Los Angeles, California in the US. She is presently undertaking a research project on the epigenetic effects of the immortality herbs in the Chinese materia medica. LauraKellyLAC@gmail.com

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