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UConn’s Henry Furneaux on the Role of microRNAs in Human Behavior

Henry Furneaux
Associate professor, molecular, microbial, and structural biology, University of Connecticut Medical School
Associate professor, neuroscience, Cornell University Graduate School of Medical Sciences — 1996-2000
Assistant professor, neuroscience, Cornell University Graduate School of Medical Sciences — 1989-1995
Postdoc, Sloan-Kettering Institute — 1984-1987
Postdoc, Albert Einstein College of Medicine — 1979-1984
PhD, biochemistry, University of Aberdeen, Scotland — 1978
BSc, biochemistry, University of Aberdeen — 1975

At the University of Connecticut, Henry Furneaux investigates how microRNAs function and impact human behavior. In September, he received a grant from the National Institute on Drug Abuse to examine cannabinoid receptor microRNAs and their relationship to addictive disease.
This week, RNAi News spoke with Furneaux about his research and where it is leading.
Let’s start with an overview of your lab at UConn.
[At Sloan Kettering, we discovered] the protein that regulates messenger RNA stability … the HuR protein. That works to regulate messenger RNAs by binding to a short AU-rich element, which was one of the classic elements that regulate messenger RNA expression. We’ve been working on that [at UConn], but when we saw the increasing interest in siRNAs, and like everybody else figured that siRNAs must be using some endogenous pathway like microRNAs, we shifted our attention to microRNAs.
So the lab works on the mechanism of action of microRNAs. Kristen Felice works on how Argonaute2 works, and we use let-7 as a model microRNA in various model target substrates. David Salzman works on how the precursor duplex is unwound.
The area that the grant is on is a new area for us. Most human sequences are identical in the open reading frame. But we have significant variation in untranslated regions. So we figured that some of the polymorphisms that have been identified in the 3’ UTR, and have been assumed to be non-functional because they’re in the 3’ UTR, [might] be within microRNA-binding sites. [As a result, these] might actually be functional polymorphisms that disrupt microRNA regulation and therefore contribute to diversity of gene regulation in humans.
The first area that we looked at are genes involved in human behavior since we figured that if this phenomenon existed then that’s where we were going to find it first. Kevin Jensen initiated a collaboration with Jonathan Covault and Hank Kranzler, who have been studying behavior genes in addictive disease … and looked at a list of genes involved in human behavior — cannabinoid receptor was the first one, and now we’ve looked a many genes [including] all the serotonin receptors, the enzymes that make serotonin, dopamine — and we found that quite frequently you can find the polymorphism that looks like it would disrupt a putative microRNA target site.
To see whether that is the case, we sub-cloned those sites and assayed them by luciferase expression using the standard microRNA technology, and indeed in quite a few cases a single point mutation, oftentimes very close in the seed sequence, can abrogate the effect of the microRNA on that element. In more recent studies that we’re preparing for publication, we’ve seen that there is a correlation between these polymorphisms and abherent human behavior … [in] various human populations [using] various measurements of human behavior — typically students … answering questionnaires.
We figured that this is probably a major source of variation and we’ve started now looking in tumor cells for somatic mutations in these sites. In another study we’ve looked at BRCA1, which is a tumor susceptibility gene, and have found that you can find alterations there that make a microRNA work better and thus turn off BRCA1. Perhaps, [this] may lead to an increased susceptibility to cancer. As you might know, there are many people that have a hereditary component in terms of ovarian and breast cancer but don’t have a mutation in the places where people have looked. This is not to say that this is the only gene that confers susceptibility but what we’re saying is that there are new places to look for mutations that haven’t been looked at before.
Can you talk about the details of the cannabinoid receptor project?
That was the first [target] we looked at. We identified a single nucleotide change, and indeed that polymorphism, which you find particularly in African-Americans as it turns out, modulated the activity of that microRNA. Ironically, that was one of the more subtle effects — it was about a two-fold effect. [In] the other [targets] we’re looking at there are huge effects — 10-, 20-fold effects.
We’re definitely going to pursue [the cannabinoid receptor effort]. We’re going to look at various populations who might be addicted to cannabis, for example, and see whether the polymorphism that releases the suppression by the microRNA on the receptor correlates with susceptibility to addictive disease.
Should that be the case, would it be a point for intervention?
Oh sure. We’re trying to develop animal models where one could theoretically introduce a new microRNA that would be complementary to the mutated messenger RNA target site and should be able to rescue it. We’ve done that in vitro — we’ve actually taken a microRNA that we’ve mutated to make it anneal to the variant target site, and that does work. In terms of humans, this is farther down the line, but we want to do these experiments in rats and introduce microRNAs directly into the brain.
In your NIH grant, you made mention of antagomirs. Those were developed by Rockefeller University researchers (see RNAi News, 11/4/2005). Are you collaborating with them?
Actually, when [Rockefeller University researchers] first reported these compounds … Jon Shubert-Coleman, a student in the lab had reconstituted microRNA action and we started making antagomirs ourselves and testing them in vitro. So we have also designed antagomirs, and there’s not much difference [with the ones out of Rockefeller]. The pioneering effort is clearly [from Rockefeller] but we’ve made some little kinks to that — we’ve changed the sequences and so forth, and some of our antagomirs work a little bit better than the current store-bought variety.
Is your newer work with serotonin and dopamine also looking at addiction or is it in things like depression?
This is so prevalent, we were actually surprised. Of the original list of genes we looked at, something like 20 percent had identifiable polymorphisms that would likely alter microRNA regulation. We haven’t proven all of those — we’re working our way down the list — but it really seems to be a prevalent mechanism. And yeah, in terms of serotonin receptor and serotonin transporter, we want to look at patients who are resistant to depressive medications, for example, or who are overly sensitive.
We are very interested in establishing interactions with groups that have already collected DNA from populations like that — schizophrenia, depression, anxiety — and we’d be very keen to see what our polymorphisms do in those particular populations.
And in theory intervention with an antagomir could be done?
Exactly, in the cases where the polymorphism /mutation results in increased microRNA activity
At this point, is this work in-house or do you have collaborators from academia or industry?
This is basically a project started by a graduate student, Kevin Jensen. We have our immediate collaborators, Jonathan Covault and Hank Kranzler, who are clinical investigators here and are part of the Alcohol Research Center at the University of Connecticut. But as you can imagine, we are branching out. In particular, we have a very good interaction with the Neag Comprehensive Cancer Center here, and that’s where we’d be looking at similar phenomena in cancer genes. In addition, investigators from the vascular biology center are also interested in finding polymorphisms that may compromise microRNA regulation of genes involved in cardiovascular biology.

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