Mathies Laura D, Blackwell GinaMari G, Austin Makeda K, Edwards Alexis C, Riley Brien P, Davies Andrew G, Bettinger Jill C
Departments of Pharmacology and Toxicology.
Psychiatry, and.
Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):3032-7. doi: 10.1073/pnas.1413451112. Epub 2015 Feb 23.
Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.
酒精滥用是一个普遍且严重的问题。了解影响滥用可能性的因素对于开发有效的治疗方法至关重要。滥用行为的发展受到遗传和环境两方面的影响，但确定具体的致病因素一直很困难，部分原因在于致病因素复杂的遗传结构以及环境刺激对该遗传易感性表达的影响。基因表达的表观遗传修饰可能是遗传和环境敏感型表达变异的基础，并且表观遗传调控与成瘾的发展有关。在这里，我们确定了开关缺陷/蔗糖不发酵（SWI/SNF）染色质重塑复合物在调节线虫秀丽隐杆线虫对酒精的行为反应中的作用。我们发现，SWI/SNF组件在成体中对于正常的乙醇行为反应是必需的，并且不同的SWI/SNF复合物调节乙醇急性反应的不同方面。我们表明，SWI/SNF亚基SWSN-9和SWSN-7在神经元和肌肉中对于乙醇急性功能耐受性的发展是必需的。在人群中检查SWI/SNF复合物成员与酒精依赖诊断的关联，发现SWI/SNF复合物成员中的等位基因变异，这表明SWI/SNF靶标调控的变异可能影响发生滥用障碍的倾向。总之，这些数据强烈表明与SWI/SNF复合物成员相关的染色质重塑在不同门生物对酒精的行为反应中起作用。
