It’s the classic dilemma — do you eat that delectable morsel of cheese now or save it for later? If you tend to lack self-control, you might be at higher risk of impulsive or aggressive behavioral disorders, which have been linked to genes in the monoamine oxidase (MAO) family. A new study from the lab of Gustavo Turecki (McGill University, Quebec, Canada) toys with the idea that dysregulation of MAOA is guided by a previously unknown lncRNA in the brain.
Using brain (dentate gyrus) tissue from people who died by suicide, and a custom DNA methylation microarray, the talented team explored the epigenetic profile of two MAO genes (A and B) and the noncoding region between them and found that:
- An intergenic region (IGR) containing 12 CpGs is less methylated in the brains of impulsive-aggressive suicides compared to controls
- Hypomethylation is specific to neuronal nuclei separated by fluorescence activated cell sorting (FACS)
- Expression of the MAOA gene is lower in the suicide group, as measured by qPCR
The clever crew noticed that the pattern of methylation in the IGR was similar to what is usually found in promoters, and hypothesized that a non-coding RNA might be expressed nearby. They used 5’ and 3’ rapid amplification of cDNA ends (RACE) to identify a novel transcript that they called MAALIN, which was more expressed in the suicide group. They decided to take a deep dive into MAALIN regulation and function and found that:
- The differentially methylated sequence can drive MAALIN expression in luciferase assays, but only when it is not methylated
- There is less H3K27me3 present at the promoter in dentate gyrus tissue from suicides compared to controls
- Viral overexpression of MAALIN decreases MAOA expression in neural progenitor cells
- On the other hand, CRISPR/Cas9 knockout of MAALIN increases MAOA
Next, the brainy bunch decided to pounce on their hypothesis that MAALIN regulates aggressive behaviors, and injected HSV-MAALIN vectors into the dentate gyrus of mice. The overexpression decreased MAOA expression in the same brain area and decreased the amount of time it took the mice to attack an intruder in their home cage.
Senior author Gustavo Turecki shares, “While aggressive behavior is part of our normal repertoire of behavioral responses, when pathological, it becomes a major problem for which we do not have efficient intervention tools.” Benoit Labonté, the first author on the study, adds “By identifying this novel gene, one could think of using it as a diagnostic tool for people with high impulsivity levels to develop suicidal behaviours. We can also consider for future research developing pharmacological agents acting on this pathway to treat patients with impulsivity issues often observed in addition including alcoholism, drug of abuse or gambling.”
Take a squeak peek at the original article in Molecular Psychiatry, January 2020.