Causal roles of stress kinase JNK2 in DNA methylation and binge alcohol withdrawal-evoked behavioral deficits. (February 2021)

• Record Type: Journal Article
• Authors: Yang, Mei; Barrios, Jasson; Yan, Jiajie; Zhao, Weiwei; Yuan, Shengtao; Dong, Erbo; Ai, Xun
• Is Part Of: Pharmacological research. Volume 164(2021)
• Publication Date: 2021-02
• Subjects: 5-Aza 5-Azacytidine -- 5mC 5-methylcytosine -- BAW binge alcohol withdrawal -- BAC Blood alcohol concentration -- CS conditional stimulus -- DNMT1 DNA methyltransferase1 -- EPM Elevated Plus-Maze (EPM) -- HDACs histone deacetylases -- HHS Holiday Heart Syndrome -- JNK c-Jun NH(2)-terminal kinase -- LDB Light/Dark Box -- OF Open Field -- PFC prefrontal cortex -- US unconditioned stimulus; Stress kinase JNK2 -- Binge alcohol withdrawal -- Behavioral deficits -- DNA methylation -- DNA methyltransferase 1 -- Prefrontal cortex; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.105375
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Highlights: Stress Kinase JNK2 drives Binge alcohol withdrawal-evoked behavioral deficits. JNK2-evoked DNA hypermethylation is responsible for BAW evoked behavioral deficits. The JNK2 drives DNA hypermethylation via the c-JUN- Dnmt1 signaling pathway Abstract: Excessive binge alcohol intake is a common drinking pattern in humans, especially during holidays. Cessation of the binge drinking often leads to aberrant withdrawal behaviors, as well as serious heart rhythm abnormalities (clinically diagnosed as Holiday Heart Syndrome (HHS)). In our HHS mouse model with well-characterized binge alcohol withdrawal (BAW)-induced heart phenotypes, BAW leads to anxiety-like behaviors and cognitive impairment. We have previously reported that stress-activated c-Jun NH(2)-terminal kinase (JNK) plays a causal role in BAW-induced heart phenotypes. In the HHS brain, we found that activation of JNK2 (but not JNK1 and JNK3) in the prefrontal cortex (PFC), but not hippocampus and amygdala, led to anxiety-like behaviors and impaired cognition. DNA methylation mediated by a crucial DNA methylation enzyme, DNA methyltransferase1 (DNMT1), is known to be critical in alcohol-associated behavioral deficits. In HHS mice, JNK2 in the PFC (but not hippocampus and amygdala) causally enhanced total genomic DNA methylation via increased DNMT1 expression, which was regulated by enhanced binding of JNK downstream transcriptional factor c-JUN to the DNMT1 promoter. JNK2-specific inhibition either by an inhibitor JNK2I or JNK2 knockout completely offset c-JUN-regulated DNMT1 upregulation and restored the level of DNA methylation in HHS PFC to the baseline levels seen in sham controls. Strikingly, either JNK2-specific inhibition or genetic JNK2 depletion or DNMT1 inhibition (by an inhibitor 5-Azacytidine) completely abolished BAW-evoked behavioral deficits. In conclusion, our studies revealed a novel mechanism by which JNK2 drives BAW-evoked behavioral deficits through a DNMT1-regulated DNA hypermethylation. JNK2 could be a novel therapeutic target for alcohol withdrawal treatment and/or prevention.