Bohnsack John Peyton, Zhang Huaibo, Wandling Gabriela M, He Donghong, Kyzar Evan J, Lasek Amy W, Pandey Subhash C
Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA.
Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
Sci Adv. 2022 May 6;8(18):eabn2748. doi: 10.1126/sciadv.abn2748. Epub 2022 May 4.
Adolescent binge drinking is a major risk factor for psychiatric disorders later in life including alcohol use disorder. Adolescent alcohol exposure induces epigenetic reprogramming at the enhancer region of the activity-regulated cytoskeleton-associated protein (Arc) immediate-early gene, known as synaptic activity response element (SARE), and decreases expression in the amygdala of both rodents and humans. The causal role of amygdalar epigenomic regulation at SARE in adult anxiety and drinking after adolescent alcohol exposure is unknown. Here, we show that dCas9-P300 increases histone acetylation at the SARE and normalizes deficits in expression, leading to attenuation of adult anxiety and excessive alcohol drinking in a rat model of adolescent alcohol exposure. Conversely, dCas9-KRAB increases repressive histone methylation at the SARE, decreases expression, and produces anxiety and alcohol drinking in control rats. These results demonstrate that epigenomic editing in the amygdala can ameliorate adult psychopathology after adolescent alcohol exposure.
青少年酗酒是日后包括酒精使用障碍在内的精神疾病的主要风险因素。青少年接触酒精会在活动调节细胞骨架相关蛋白（Arc）即早基因的增强子区域诱导表观遗传重编程，该区域被称为突触活动反应元件（SARE），并降低啮齿动物和人类杏仁核中的表达。青少年酒精暴露后，SARE处杏仁核表观基因组调控在成人焦虑和饮酒中的因果作用尚不清楚。在这里，我们表明dCas9-P300增加了SARE处的组蛋白乙酰化，并使表达缺陷正常化，从而减轻了青少年酒精暴露大鼠模型中的成人焦虑和过度饮酒。相反，dCas9-KRAB增加了SARE处的抑制性组蛋白甲基化，降低了表达，并在对照大鼠中产生焦虑和饮酒行为。这些结果表明，杏仁核中的表观基因组编辑可以改善青少年酒精暴露后的成人精神病理学。
