Transgenerational Epigenetics? It’s Complicated.

“We need to be careful in thinking it’s all about genetics – it’s not all about genetics. We need to take into account: epigenetics.”   ~ Paolo Sassone-Corsi

[photo credit: John Hersey of NYTimes]

So I think we’ve established this much: in order to understand the biological-behavioral interface, we need to better understand epigenetic processes. More specifically, we need to know: Which epigenetic marks are transmitted transgenerationally? And how are they?  Which marks are stable and which marks can be erased? What genes are susceptible to de novo methylation and what environmental factors (chemical, nutritional, hormonal, behavioral…) mediate these effects? Furthermore, how do these processes vary over space and time? [or in scientific jargon: what is the spatio-temporal specificity of these marks?]

These are just some of the questions scientists are facing as they attempt to break ground in the emerging field of epigenetics in neuroscience. Of course, this in no way implies the mechanism itself is new – to call it emerging simply means our awareness of this as a mechanism is emerging. So take any of the questions above, try to crack it open and what you’re likely to get (in addition to some hopefully useful data): even more questions.

Okay, so it’s complicated. What’s new, right? It seems obvious to state that the brain, genetic networks and the relationship between all these pieces is, well, complex – and yet, sometimes it’s the obvious truths that need to be stated. Truths that are obvious, tend over time, to be forgotten as we proceed along the investigative journey – especially when it comes to using (necessarily) reductionist methods to discover the functional components of a larger and complex, whole.

So this morning, at the minisymposium “Transgenerational Inheritance and Epigenetics: Animal Models of Neuropsychiatric Disease” that’s exactly what Dr. Tracey Bale, researcher at the University of Pennysylvania and chair of panel, did. She then launched into the data her lab has begun to unearth in an attempt to answer the following question:

What is the critical window within which induced maternal stress will affect male offspring at various gestational periods?

To answer this question, her group presented various stressful stimuli to the animals, then ran behavioral assays on the male offspring during early, middle, and late gestational periods. They found that the behavioral readouts (anxiety tests, spatial learning, etc) were sex-specific (hinting at an imprinting mechanism). They followed this observation with a scan to look at genes which showed sex-specific differentiation in expression. 96 genes revealed sex-specific expression, 32 of which appeared “demasculanized” (assessed based on angio-genital distance and testes-weight measures). This observation that the up or down regulation of certain genes was sex-specific, prompted the group to look at microRNAs.

Why? MicroRNAs (miRNA) regulate about 30% of protein-coding genes and they are enriched on the x-chromosome. Also, miRNAs are present in high levels in sperm (facilitating a mechanism whereby maternal stress effects can be transmitted through the germline and result in a measurable phenotype in the male offspring as adults). What did they find? 4 out of 329 miRNAs scanned for sex-specific responses to stress showed changes in expression levels. They went on to discover that these 4 miRNAs had one major common gene target (with various other targets as well) How’s that for specificity?

So what does it all mean? miRNAs can target gene expression in the brain of males in the F2 generation – in other words: this is proof that stress-mediated epigenetic changes can be transmitted across generations. I’ll let you chew on the public health implications of that one.

Until Tomorrow!

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4 Responses to Transgenerational Epigenetics? It’s Complicated.

  1. Grace says:

    Like you mentioned, the specificity of one of the major genes targeted by the 4 miRNAs was pretty striking in the F2 generation – with a profound decreased expression in the miRNAs corresponding to an increased expression in the specific gene. Wish I could remember the gene name, but I do recall that it regulates the expression of luteinizing hormone and follicle stimulating hormone.

    With all the research placing the “burden” of prenatal environment/care on females, it’s nice to hear that males matter too! It was also interesting to see Frances Champagne’s work regarding the influence of the “father” on maternal investment and care of the offspring. It would be interesting to see whether, after establishing a transgenerational effect of low licking and grooming offspring females as a result of a socially isolated “father,” the cycle can be broken by pairing an enriched male with a low licking/grooming offspring female.

  2. neurobloggie says:

    Grace: Thanks for taking the time to read and comment! I’m so glad you wrote about Frances Champagne’s presentation as I was late to the symposium and had missed that talk! The other talks were also great, but unfortunately can only cover so much in one post. I definitely agree it’s nice the paternal effects are being looked at too. Are you going to try that experiment? 🙂

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