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Regulation of impulsive and aggressive behaviours by a novel lncRNA

Abstract

High impulsive and aggressive traits associate with poor behavioural self-control. Despite their importance in predicting behavioural negative outcomes including suicide, the molecular mechanisms underlying the expression of impulsive and aggressive traits remain poorly understood. Here, we identified and characterized a novel long noncoding RNA (lncRNA), acting as a regulator of the monoamine oxidase A (MAOA) gene in the brain, and named it MAOA-associated lncRNA (MAALIN). Our results show that in the brain of suicide completers, MAALIN is regulated by a combination of epigenetic mechanisms including DNA methylation and chromatin modifications. Elevated MAALIN in the dentate gyrus of impulsive-aggressive suicides was associated with lower MAOA expression. Viral overexpression of MAALIN in neuroprogenitor cells decreased MAOA expression while CRISPR-mediated knock out resulted in elevated MAOA expression. Using viral-mediated gene transfer, we confirmed that MAALIN in the hippocampus significantly decreases MAOA expression and exacerbates the expression of impulsive-aggressive behavioural traits in CD1 aggressive mice. Overall, our findings suggest that variations in DNA methylation mediate the differential expression of a novel lncRNA that acts on MAOA expression to regulate impulsive-aggressive behaviours.

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Fig. 1: Methylation of the MAOA–MAOB intergenic region in dentate gyrus.
Fig. 2: Characterization of the MAALIN transcript.
Fig. 3: Effect of methylation on the transcriptional activity of the MAOA–MAOB intergenic region.
Fig. 4: Effect of MAALIN in vitro overexpression and knock out on MAOA expression in NPCs 35 days post differentiation.
Fig. 5: Behavioural and functional impact of in vivo MAALIN overexpression.

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Acknowledgements

GT holds a Canada Research Chair (Tier 1) and a NARSAD Distinguished Investigator Award. He is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374 and EGM141899), by the FRQS through the Quebec Network on Suicide, Mood Disorders and Related Disorders. BL holds a Sentinelle Nord Research Chair, is supported by a NARSAD young investigator award, a CIHR (SVB397205) and Natural Science and Engineering Research Council (NSERC; RGPIN-2019-06496) grants and receives FRQS Junior-1 salary support; this work was also made possible by resources supported by the Quebec Network on Suicide, Mood Disorders and Related Disorders.

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BL, GT, NM and MJM planned the experiments, wrote the manuscript and supervised the studies. BL conducted and supervised all experiments and analysed all data. KA, TB, GM, VY and JY participated in the experiments. SAG, SJR and EJN provided help and support for the design and interpretation of the animal experiments. LN, DC, CG, JPL, RET and GC contributed to the experiments. RLN provided viral constructs.

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Correspondence to Benoit Labonté or Gustavo Turecki.

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Labonté, B., Abdallah, K., Maussion, G. et al. Regulation of impulsive and aggressive behaviours by a novel lncRNA. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-019-0637-4

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