FASD, methylation and miRNA: changing the “volume” on gene expression

It’s a terrible and yet all too frequent thing when a child is born with fetal alcohol spectrum disorders (FASD). While each child can have a different collection of physical and cognitive symptoms, they will suffer with them for their entire lives. There is no definitive test for FASD and there is no cure, only treatments for individual symptoms. And since indicators like memory difficulties and impulse control aren’t obvious at birth, they can be caught too late or misdiagnosed when the child starts school.

These symptoms exist, in part, because the child’s genetic instructions are carried out (“expressed”) differently than in a healthy child, as a result of the mother’s alcohol consumption while she was pregnant.

Of mice and humans

Ben Laufer preparing a sample in the labFor about 15 years, Western University’s Dr. Shiva Singh, his team and other researchers around the world have been studying FASD by using mice that prefer alcohol to water. One of the most recent additions to the FASD body of knowledge comes from the Ph.D dissertation of one of these team members, Ben Laufer, who studied the interactions of two of the epigenetic tags involved in the disorder. Epigenetic tags function as a long-term mechanism by which profiles of gene expression can be developmentally regulated in stem cells and are also repurposed for brain function.

As with humans, mice from alcohol-­‐preferring mothers can develop symptoms similar to FASD if exposed during pregnancy. Earlier research on these mice showed that certain genes are over or under-­‐expressed, as if someone turned a volume dial up or down during fetal development.  As well, 80 percent of the under or over-­‐expressed mouse genes are involved in neurodevelopment, metabolism, and others systems linked to FASD.

Since the brain has been the focus of FASD research, gene expression related to it has not been studied as deeply in humans as in mice. However, Laufer not only looked more closely at the mechanics of prenatal alcohol exposed mouse gene expression, he replicated some of his results with FASD humans, using buccal (mouth) swabs collected from children by Dr. Joachim Kapalanga.

The miRNA volume control to the methylation switch

If the genome is like a musical instrument, epigenetics are like the sheet music for it. Depending on environmental influences, the “music” may be played different ways by the epigenetic messages – tags – that control gene expression.

There are several tags involved in gene expression, but Laufer’s thesis concentrated  on the interaction of two. The first, DNA methylation, is a tag that works like an off/on switch for each gene, including the genes that cause some the symptoms of FASD. The second tag, microRNA (miRNA) is the “volume” controller.

There is an identified cluster of genes that are involved in FASD. However, each person (or mouse) with the disorder may have a different combination turned off or on through methylation. Laufer’s study of miRNA expression in mice narrowed the possible diagnostic field by revealing a number of genes in the FASD that are controlled by miRNA. Some of his results in mice were similar to the results from the FASD children, and in both mice and humans  there was a pattern of methylation shutting off genes that give the cells of the brain their individual identities.

There are hints about other tags, too. miRNA is part of a larger group of RNA tags known as non-­‐coding RNAs (ncRNAs), which all serve different functions in gene expression. Within the cluster of FASD genes, Laufer documented other types of ncRNA expression, with 20 percent linked to three key neurodevelopmental parts of the mouse genome – again, with some similar results in humans.

In simple terms, Laufer’s findings suggest that miRNA controls the strength of gene expression that is altered in the long-term by alcohol intake, and he identified the genes that miRNAs target. He also gained additional knowledge for deeper research into the DNA methylation profile of FASD.

Right now, the main way to diagnose children with FASD is by observing a child’s physical and developmental traits that may – or may not – be caused by the condition. Laufer’s fascinating findings are important because they will allow researchers to further isolate and test genes and epigenetic tags related to FASD. Those next steps could soon lead to a clear and accurate tool for early FASD diagnoses, or even new treatments.

Dr. Singh is a Distinguished University Professor at Western University, a professor in the Department of Biology, and an Associate Scientist at the Child Health Research Institute at the London Health Sciences Centre. His research has been funded by NSERC, CIHR, OMHF, SSO, the Bill Jefferies Schizophrenia Endowment Fund, and the University of Western Ontario.

Dr. Ben Laufer defended his thesis at Western this summer. He is now on a Canadian Institutes of Health Research post-doctoral fellowship at the University of California Davis.