Researchers have found that the regulation of a specific gene located in an area of the brain linked to depression and drug addiction can reduce the way someone responds to drugs and stressful situations. A mouse study that focused on the epigenetic regulation of a single gene was carried out at the Icahn School of Medicine at Mount Sinai and was recently published in Nature Neuroscience.
Earlier research supports a connection between epigenetic regulation and diseases related to depression and drug addiction in both humans and animals. Specialized proteins known as transcription factors, which bind to certain DNA sequences, are involved in this regulation by either stopping or encouraging the expression of a particular gene.
The team of scientists looked at mice models of human stress, addiction and depression and applied engineered transcription factors to the mice’s nucleus accumbens – a part of the brain related to the reward circuit – at one gene known as FosB. According to earlier research, this gene has previously been linked to depression and addiction. The researchers discovered that the mice were less likely to develop a cocaine addiction and were more resilient against stress due to the alteration of the one gene by engineered transcription factors.
Every cell in the body contains DNA, the genetic code or set of instructions necessary for survival, growth and development. The sequences that make up the genetic code are turned into messages that dictate which proteins should be made and which function should be carried out. Most genes are inactive, despite every cell containing DNA that can code for every gene. The gene’s expression is dependent on specialized proteins, or transcription factors, that regulate the DNA structure inside of the cell, which then activates some genes and represses others. The chemical modification of DNA and the modification of histones, which are packaged around the DNA and adjust their shape in order to make segments of DNA available, are both epigenetic mechanisms by which transcription factors act.
“Earlier work in our laboratory found that several transcription factors and downstream epigenetic modifications are altered by exposure to drugs or to stress and that these changes, in turn, control gene expression,” explained the scientist who led the study, Eric J. Nestler, MD, PhD, Nash Family Professor, Chair of the Department of Neuroscience and Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai. “But because such epigenetic regulation occurs at hundreds or thousands of genes, until now it had been impossible to determine the difference between the mere presence of an epigenetic modification and its functional relevance to neuropsychiatric disease.”
Elizabeth A. Heller, PhD, the lead author of the paper, aimed to address this issue by developing a new, innovative way to control the epigenetic regulation of the FosB gene. Dr. Heller applied engineered transcription factors known as Zinc Finger Proteins (ZFPs), which were designed to target only one gene out of 20,000. She did this by inserting them in a virus and injecting the virus into the nucleus accumbens.
The results displayed that once ZFPs bound to the gene, histones were modified by the FosB-ZFPs in the area of the FosB gene, which either activated or repressed expression. Specifically, the researchers reported that, at the FosB locus in the nucleus accumbens, histone methylation or histone acetylation “was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery.”
In mice, FosB gene expression in nerve cells is necessary and sufficient for responsiveness to drugs and stress. The researchers found that turning on FosB is associated with increased drug sensitivity and stress resilience. This activation can be changed as a result of exposure to relevant stimuli in the mice brains that were modeling human depression, stress and addiction as well as in the brains of humans addicted to drugs or experiencing depression.
“While drug addiction and depression are hereditary diseases that regulate gene expression in the brain, the field has yet to uncover relevant mutations in gene sequences that underlie these disorders,” said Dr. Heller. “Therefore, we focused on changes in gene structure to probe the mechanism of action of such changes in drug and stress sensitivity. Our data is a critical first step towards developing novel therapeutics to combat these neuropsychiatric diseases. In addition, the use of engineered transcription factors has broad implications outside of neuroscience because epigenetic gene regulation underlies many diseases, including most forms of cancer.”
Source: Learn all about it and read more about their findings here: Elizabeth A Heller, et al. Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nature Neuroscience. 2014.
Reference: Changes in a Single Gene’s Action Can Control Addiction- and Depression-Related Behaviors. Ichan School of Medicine at Mount Sinai. 2014.
