Posted by: Harry | November 18, 2011

SfN 2011 things I wish I saw #1: Sex differences in the epigenetics of stress-related disorders!

Because the conference is so busy, and because it imposes so many conflicting demands on my time, it was impossible to make every talk and poster. For the next little while, I will blog about things I wish that I saw at Neuroscience, but for various reasons did not.

Epigenetics is a very interesting field, though for whatever reason, some find it unapproachable and intimidating. This could be due to the fact that the field is just so darn inclusive. If you dissect the etymology of the word, you see the prefix epi- which simply means “above” or “upon” and -genetics, which means, well genetics. So in the broadest sense, epigenetics concerns things that relate to genetics (in practice: how genes are expressed) that exist over and above the genetics themselves. Since the field is so broad, and constitutes yet another layer of molecular complexity on top of our already confusing genetic code, it may seem difficult to apprehend.

Your genes are, after all, fixed at conception. But clearly that is not the entire story, as gene expression is regulated in a tissue dependent fashion (your liver expresses liver genes, your brain expresses brain genes, etc., in spite of the fact that each of them possesses a nucleus containing the same DNA). Gene expression is also regulated by experiential factors. Environmental factors during development, or even in adult life can affect the expression of genes in a long-term fashion. What’s interesting, from the point of view of scientists studying these phenomena, is that the changes tend to last much longer than the initial stimulation (whatever it was). So the question we’re dealing with is the following: what types of molecular changes underlie these long-term effects, and how do they relate to illnesses we face?

Researchers from the Mt. Sinai School of Medicine in NY discussed this topic in a minisymposium. Mental illness is an important topic for epigenetic studies, since often times the most challenging illnesses persist for long periods, perhaps indefinitely. It is possible, then, that epigenetic factors are involved in this persistence. The series of studies here took an interesting approach by focusing on models of depression that only affected female animals (this is a topic that Rim is quite interested in, but I’m blogging about it, so too bad for her). This is a very sensible approach, since depression is actually more common in females (though I dislike making sweeping generalizations, this does seem to hold up). In this model, mice were subjected to various mild stressors given at various, unpredictable times during the day. This treatment induced behaviors reminiscent of depression and anxiety in female, but not male mice.

After this treatment they found that stressed females showed an upregulation of two proteins involved in “stamping in” epigenetic marks in DNA. These proteins (one is an enzyme, the other a DNA binding protein) are crucial in DNA methylation, a type of epigenetic mark that involves attaching methyl groups to the points on the DNA thereby reducing transcription of nearby genes. To further cement this case, the authors used various techniques to artificially upregulate these methylation related genes, thereby mimicking the effects they saw in the stressed animals. Indeed, this manipulation actually made males more like females in their response to stress. On the other hand, blocking these seemed to have anti-depressent effects in females. The implication of all this, I suppose, is that since methylation is presumably being increased, genes that are protective against stress induced depression are being silenced, leading to the depressed phenotype.

What’s interesting about this study is that it addresses the very important issue of sex differences in mental illness. Well actually sex differences exist in practically everything, and more should be made of it. But since mental illnesses are particularly sexually dimorphic, studies that bring sex into the picture should hopefully be getting more and more common.


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