Environmental Impact

Research in behavioral epigenetics is seeking evidence
that links experience to biochemistry to gene expression
and back out again.

Jasper James / Gettyimages

In the late 1970s, when Hans Reul was a student running gels on the rich soup of proteins around DNA and RNA, he found himself wondering about the function of those nongenetic molecules in his samples. “I asked my supervisor, ‘What are those proteins down there?’ he recalls. “And he said, ‘Well, they’re histone molecules. We have no clue what they’re doing. They sit in the nucleus and do something with the DNA.”

At the time, for researchers chasing links between genes and behavior, all the tools and all the promise seemed to focus on two molecules, DNA and RNA. So did depictions in the popular media of the links between genes and personality. It was the era when Nobelist Walter Gilbert, extolling the Human...

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Epigeneticists, though, focus on the up-and-down regulation of a gene’s expression, not on its differences from other alleles. And they’re interested in molecular events in the neuron’s nucleus, rather than the connections at its synapses—or the characteristics of functional brain regions.

Several years ago, for example, Moshe Szyf, Michael Meaney, Patrick McGowan and their colleagues compared the brains of 18 men who had been abused as children and later killed themselves to brains from 12 control subjects who had died suddenly of other causes and had no record of childhood trauma. Compared to the controls, the researchers reported in 2008, the suicides’ hippocampal tissue showed much higher degrees of DNA methylation in genes that encode ribosomal RNA.2 In another study the following year, they found that the brains of suicides who had not been abused as children didn’t show the same methylation pattern as those of suicides who had been: “there was no difference between nonabused suicide victims and controls.”3

So Szyf and his colleagues believe they may have a first sighting of the ultimate goal of behavioral epigenetics: a precisely documented chain of connection from experience (child abuse) to measurable changes in gene expression in the brain (methylation of rRNA genes) to a behavior (suicide). “Although our findings are largely based on correlational studies indicating an association between psychopathology and methylation,” they wrote in their 2008 paper, “these data are consistent with growing evidence suggesting that alterations in cytosine methylation mediate biological processes associated with psychopathology.”

This kind of work raises the prospect of new drugs to treat behavioral disorders and new diagnostic methods, Szyf says: if a particular methylation pattern is tightly associated with vulnerability to suicidal thoughts, it might be possible to detect people who are at risk and intervene to help them.

Of course, taking cells from a living person’s hippocampus isn’t possible, and would be subject to ethical challenge. So some behavioral epigenetics labs have turned to blood assays, on the hypothesis that immune-system cells can serve as proxies for neurons.

“The immune system is highly interactive with the brain,” Szyf says, and he asserts that a number of labs have already “associated T-cell methylation with behavior.” The next question, he says, is: “If you can change behavior, will you also change T-cell methylation?’’ Richard E. Tremblay, of University College Dublin and the University of Montreal, with whom Szyf has collaborated, has been working on that question.

Tremblay and his colleagues recently analyzed blood samples from a cohort of boys, age 6 to 12, whose behavior suggested they were likely to become chronically aggressive, and compared them to more typical boys. The researchers’ preliminary analysis, Tremblay says, indicates that the high-aggression group tends, when compared to the more typical children, to have lower cytokine levels, and the genes that code for those cytokines, examined in T cells, have more methylated alleles.4 “The developmental pattern of these immune-system differences will be important to study,” Tremblay writes in an e-mail. “Are the differences in gene methylation and expression at the origin of the behaviour differences or are they the product of the behaviour differences?”

This sort of work illustrates why behavioral epigenetics seems to demand a different conceptual mindset in neuroscience—a focus on molecular modifications in the cell’s nucleus, rather than on interneuronal circuitry or gross anatomy. A 2000 study found that London cab drivers, who have to memorize a detailed map of a giant city, have larger-than-usual hippocampi5—a correlation between anatomy and behavior that is a familiar type of neuroscience result, Szyf notes. But to his mind, the question it raises is: “Why is the hippocampus big?” Where are the instructions to grow encoded, and how are they triggered, at the level of DNA?

Epigenetics and memory

Of course, it has long been obvious that some sequence of physiological events must link a human being’s experiences to one’s DNA: people get depressed or develop a habit of violence because of biochemical signals in the brain that trigger molecular activity in the nuclei of neurons, shutting down some genes and increasing the activity of others. If that weren’t the case, people’s experiences could not affect their behavior.

What’s new and exciting, say the field’s boosters, is their recent progress in replacing this very general outline with biochemical details. Their goal, not yet reached, is to lay out every link in the causal chain that leads from a person’s experience to a neurotransmitter, then to a particular gene, then to a specific molecular modification of protein or DNA that affects that gene, and then back out from gene products to neuronal signaling to a person’s thoughts, feelings and actions.

The time scale—whether, for example, methylation lasts for the few hours of a short-term memory, for years as a long-term memory, or across generations as a tendency to get diabetes—isn’t the researchers’ main concern. C.H. Waddington’s founding definition of epigenetics—transgenerational inheritance that isn’t dependent on DNA sequence—doesn’t fit what they do.

The processes that modify DNA and histones “were originally described genetically because what was initially studied was transgenerational inheritance and patterns of variegated gene expression,” says Ted Abel, a molecular biologist at the University of Pennsylvania who works on the relationship of epigenetic processes to mental illness and neurodegenerative diseases. “But we now know the details of the underlying biochemistry to these processes. So in my mind, the definition of what is considered an epigenetic process has expanded to include these biochemical mechanisms.”

Szyf thinks questions of heritability narrowly spotlight a single epigenetic time scale (what happens between generations), while methylation and demethylation occur at time scales ranging from seconds to hours (supporting short-term memories) to decades (supporting long-term memories), as well as generations. The emphasis on heritability is a cumbersome holdover from genetics, he says, “because in genetics, of course, everything is heritable. Do we want epigenetics to look like genetics? Why should we?”

At a 6

At the psychological level of analysis, standardized measures of behavior are scarce. Diagnoses vary from psychiatrist to psychiatrist, and the same term for a mental illness may cover different symptoms. In any large sample collected to study a mental illness, Albert writes, there are problems of “appropriateness of the ‘hyper-normal’ control group (screened for lack of mental illness and/or addiction), diagnostic variability, heterogeneity of illness and variations owing to mixed race, all of which will detract from the reliability and power of association.” Then, too, there are other mechanisms for fixing and maintaining a behavior—religion, law, tradition—which can confound attempts to link a behavior to a biochemical mark.

Meanwhile, at the molecular level, an epigenetic approach adds layers of complexity, in part because epigenetic marks don’t come simply in “on” and “off. ” “For example,” Albert wrote, “typically individual DNA methylation sites are partially methylated; hence, multiple sequences from the same cell type or tissue preparation must be run to estimate the percentage of methylated nucleotides.”

For the moment, even its biggest advocates concede that behavioral epigenetics has yet to connect all its levels of analysis. It needs, and doesn’t yet have, at least one slam-dunk demonstration of all the links in a chain from behavior to neural activity to gene expression and back out again. How, for example, do biochemical events at a neuron’s nucleus affect the synaptic signaling between neurons that is the basis for all behavior? That, Abel explains, is an open question with many interesting possible answers.

“A lot of the experiments that are carried out in this field are correlative,” Abel says. “It’s research that’s looking at marks and how those marks change after a behavior. We’re doing experiments about necessity. We haven’t really done sufficiency experiments.” But, he notes, the whole field is only a few years old. Those types of experiments are on the drawing board, and the fact that much remains to be done is actually one of the attractions of the field.

“There are a lot of big open questions now that I think I probably won’t be able to answer to my satisfaction for quite a while,” Sweatt says. “I think I’m probably going to work on that for the rest of my career.”

David Berreby writes the “Mind Matters” blog for References:

1. M. Vythilingam et al., “Childhood trauma associated with smaller hippocampal volume in women with major depression,” Am J Psychiatry, 159: 2072-80, 2002.
2. P.O. McGowan et al., “Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain,” PLoS ONE, 3: e2085, 2008.
3. P.O. McGowan et al., “Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse,” Nature Neuroscience, 12:342-48, 2009. Free F1000 Evaluation
4. R.E. Tremblay, “Understanding development and prevention of chronic physical aggression: Towards experimental epigenetic studies,” Philosophical Transactions of the Royal Society B: Biological Sciences, 363:2613-22, 2008
5. E.A. Maguire et al., “Navigation-related structural change in the hippocampi of taxi drivers,” PNAS, 97:4398-403, 2000.
6. P.R. Albert, “Epigenetics in mental illness: hope or hype?” J Psychiatry Neurosci, 35:366-68, 2010.

To view presentations from the recent Fall 2010 conference Behavioral Epigenetics, presented by The New York Academy of Sciences, The Warren Alpert Medical School of Brown University, and The University of Massachusetts Boston, please visit www.nyas.org/Behavioralepi-eB.

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