Inhibition of the G9a/GLP histone methyltransferase complex modulates anxiety-related behavior in mice

Dong-yao WANG1,2, Joel KOSOWAN1,2, James SAMSOM1,2, Laura LEUNG2, Kai-lai ZHANG2,3, Ying-xiang LI2, Yan XIONG4, Jian JIN4, Arturas PETRONIS1,2,5, Gabriel OH2, Albert H C WONG1,2
1 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
2 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
3 Department of Health Sciences, McMaster University, Hamilton, Ontario, Canada;
4 Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
5 5Institute of Biotechnology, Vilnius University, Vilnius, Lithuania
Correspondence to: Albert H C WONG:,
DOI: 10.1038/aps.2017.190
Received: 6 August 2017
Accepted: 26 November 2017
Advance online: 8 February 2018


Epigenetic gene-regulation abnormalities have been implicated in various neuropsychiatric disorders including schizophrenia and depression, as well as in the regulation of mood and anxiety. In addition, epigenetic mechanisms are involved in the actions of psychiatric drugs. Current anxiolytic drugs have significant shortcomings, and development of new medications is warranted. Two proteins, G9a (also known as EHMT2 or KMT1C) and GLP (G9a-like protein, also known as EHMT1 or KMT1D), which methylate lysine 9 of histone H3 (H3K9), could be promising anxiolytic targets. Postnatal genetic knock-out of G9a reduces anxiety-related behavior, consistent with the reduction of G9a levels by some medications used to treat anxiety (amitriptyline, imipramine and paroxetine). Conversely, there is increased anxiety-like behavior in mice with GLP haplodeficiency. We sought to determine whether two pharmacological inhibitors of G9a/GLP, UNC0642 and A-366, would have similar effects to genetic G9a/GLP insufficiency. We found that G9a/GLP inhibition with either compound reduced anxiety-like behaviors when administered to adult mice, in conjunction with decreased H3K9 methylation in the brain. In contrast, exposure to these compounds from embryonic day 9.5 (E9.5) until birth increased anxiety-like behaviors and decreased social interaction in adulthood, while H3K9 methylation was at normal levels in the brains of the adult mice. These findings reinforce genetic evidence that G9a/GLP has different effects on anxiety-like behavior at different stages of brain development, and suggest that targeting this histone methyltransferase pathway could be useful for developing new anxiolytic drugs. These data also suggest that antidepressant exposure in utero could have negative effects in adulthood, and further investigation of these effects is warranted.
Keywords: anxiety; depression; A-366; UNC0642; G9a/GLP; histone methyltransferase; epigenetics

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