Dysregulated Genes in the Brain May Add to the Risk of Opioid Use Disorder

Gene regulatory processes in the brain, such as DNA methylation and DNA hydroxymethylation, could hold the key to understanding why opioid use disorder (OUD) occurs, according to Janitza Montalvo-Ortiz, PhD, assistant professor of psychiatry at Yale School of Medicine (YSM).

In a study published in Nature Communications, Montalvo-Ortiz and investigators examined whether DNA hydroxymethylation, a process in which a methyl group (CH3) is removed from a DNA molecule to regulate expressed genes, might be making people more prone to developing OUD.

DNA methylation and DNA hydroxymethylation are epigenetic modifications. This means that, when influenced by a person’s environment and behavior, the way genes are turned “on” or “off” might be altered.

DNA hydroxymethylation is different from DNA methylation as it only occurs in the brain, predominantly in neurons, but has not yet been studied much, according to Montalvo-Ortiz.

DNA methylation is where a methyl group (CH3) is added to a DNA molecule, and subsequently becomes regulated.

According to Montalvo-Ortiz, DNA hydroxymethylation and DNA methylation need to be researched individually, particularly when studying the brain, because of the different roles they play in gene regulation. Her study is one of the first ones to examine these processes in the brain, specifically in neurons. In collaboration with Yasmin Hurd, PhD, and her laboratory at Mount Sinai in New York, the team accomplished this by using fluorescence to identify neurons.

They then isolated the DNA and studied DNA methylation and hydroxymethylation on genes on nucleotides, which are the compounds—like guanine and adenine—that make up DNA.

Their goal was to understand dysregulation of genes to help identify ways to prevent OUD, and potentially lead to new treatments and even medications for the condition.

Initially, Montalvo-Ortiz and investigators compared brains from healthy donors versus brains from individuals who had developed OUD. They looked at DNA methylation and DNA hydroxymethylation in neurons in the orbitofrontal cortex, which is located behind the eyes and involved in decision-making processes, including those related to addictive behaviors.

They found that dysregulation of DNA hydroxymethylation was observed in the brains of people who had developed OUD. “We also found that there were a lot more genes and gene networks dysregulated in DNA hydroxymethylation than DNA methylation.”

They found epigenetic dysregulation in genes involved in critical neuronal processes, as well as in genes associated with opioid function in the brain.

“We see more affected genes in the brains of people who developed OUD in their lifetime in comparison to brains of people who did not develop OUD,” she said. This means that the genes in which dysregulation occurs are essential gene networks so a person’s brain can adequately function. In turn, dysregulation can affect how opioids work in the brain.

“Not only are our genetic variants the ones that predispose individuals to suffer from opioid use disorder, but it is also the interaction with the environment and [our behavior] that result in changes in epigenetics,” said Montalvo-Ortiz. Importantly, she noted: “The fact that we identified epigenetically dysregulated genes tells you that there could be ways that we can revert those processes.”

Sheila Nagamatsu, PhD, postdoctoral associate in the Montalvo-Ortiz Lab and co-first author of the paper, analyzed the data that made it possible to identify dysregulated gene networks linked to OUD.

Montalvo-Ortiz says the findings are already providing insight on genes that are being epigenetically dysregulated, as well as on drugs that are used to treat OUD and potential novel ones that might help to treat the condition. The team looked at whether the gene products of those that had epigenetic dysregulation in the brain interacted with drugs, identifying drugs like methadone and fentanyl.

Although they know a crucial process is occurring, Montalvo-Ortiz said it’s not yet known where the epigenetic changes originate. Her hypotheses included that this could happen because of traumatic experiences that might have affected how that part of their brain developed, and/or chronic opioid usage.