MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China.
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
Mol Psychiatry. 2021 Aug;26(8):4367-4382. doi: 10.1038/s41380-019-0588-9. Epub 2019 Nov 19.
Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence.
酒精滥用是一个主要的公共卫生问题，源于遗传和环境风险因素。脑表观基因组的改变可能协调导致酒精滥用和依赖的基因表达变化。通过对人类脑组织中 DNA 甲基化的全基因组关联分析，我们鉴定出一个与酒精依赖相关的差异甲基化区域 DMR-DLGAP2。发现 DMR-DLGAP2 内的甲基化与基因型、等位基因特异性有关，并与大脑中的奖励处理有关。DMR-DLGAP2 的甲基化在体外调节了 DLGAP2 的表达，Dlgap2 缺陷型小鼠与野生型对照相比，酒精摄入量减少。这些结果表明，DLGAP2 可能是控制饮酒和依赖的遗传和表观遗传因素的接口。
