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標題: | 前額葉皮質及伏核之粒線體DNA甲基化情形與年齡增長、非法藥物及酒精使用之關聯 Mitochondrial DNA Methylation Profiling of the Human Prefrontal Cortex and the Nucleus Accumbens: Correlations with Aging, Drug Use, and Alcohol Intake |
作者: | 黃嘉宏 Chia-Hung Huang |
指導教授: | 陳為堅 Wei J. Chen |
關鍵字: | 表觀遺傳學,全粒線體基因體亞硫酸定序法,老化,非法藥物,酒精,伏核,前額葉皮質, epigenetic,whole-mitochondrial-genome bisulfite sequencing,aging,illicit drug,alcohol,nucleus accumbens,prefrontal cortex, |
出版年 : | 2023 |
學位: | 博士 |
摘要: | 研究背景:大腦運作仰賴粒線體提供大量的能量,然而目前表觀遺傳學的研究多針對細胞核染色體,僅少部分研究探討粒線體染色體之DNA甲基化情形。我們針對大腦伏核及前額葉皮質部分,分析粒線體DNA甲基化之特徵與1.該二腦區、2.老化程度、3.非法藥物及酒精使用之關聯性。
方法與結果: 我們自53位死者腦部收集伏核及前額葉檢體,以全粒線體基因體亞硫酸定序法分析甲基化程度。依血液是否檢出藥物分為無藥物組(n = 39)及藥物組(n = 14),發現無藥物組兩腦區之甲基化達顯著差異(P = 3.89 × 10-9),這些可能與腦部特殊功能相關的甲基化差異,則因施用藥物而縮小;其次,我們發現甲基化程度與年齡呈正相關(R2 為0.34於伏核,0.37於前額葉),施用非法藥物會加速老化,且以施用愷他命最為明顯;最後,我們篩選與用藥相關之甲基化點位,這些點位可以有效區分藥物組與對照組之差異(AUC達0.88於伏核,AUC達0.94於前額葉)。此外,我們改以血液是否檢出酒精及酒精來源將此53位死者重新分組至無酒精組(n = 34)、飲酒組(n = 9)及死後發酵組(n = 10),發現飲酒組的甲基化情形與無酒精組及死後發酵組均達顯著差異(AUC達0.89於伏核,AUC達0.94於前額葉),兩腦區對長期飲酒之敏感程度不同,且長期飲酒可能造成伏核粒線體的甲基化程度整體降低。 結論: 粒線體於不同腦區之間有不同的甲基化情形,且甲基化程度隨年齡增長而逐漸增加,並受非法藥物及酒精所影響。我們認為這是首件的研究報導指出人腦之粒線體DNA甲基化之重要性。 Background: Despite the brain’s high demand for energy, research on its epigenetics focuses on nuclear methylation, and much of the mitochondrial DNA methylation remains seldom investigated. With a focus on the nucleus accumbens (NAcc) and the prefrontal cortex (PFC), we aimed to identify the mitochondrial methylation signatures for 1) distinguishing the two brain areas, 2) correlating with aging, 3) reflecting the influence of illicit drugs and alcohol on the brain. Result: We collected the brain tissue in the NAcc and the PFC from the deceased individuals without (n = 39) and with (n = 14) drug use, and used whole genome bisulfite sequencing to cover cytosine sites in the mitochondrial genome. We first detected differential methylations between the NAcc and the PFC in the non-users group (P = 3.89 × 10-9). These function-related methylation differences diminished in the drug-positive due to the selective alteration in the NAcc. Next, we found the correlation between the methylation levels and the legal ages in the non-users group (R2 = 0.34 in the NAcc and 0.37 in the PFC). The epigenetic clocks in illicit drug users, especially in the ketamine users, were accelerated in both brain regions by comparison with the non-users. Then, we summarized the effect of the illicit drugs on the methylation, which could significantly differentiate the drug users from the non-users (AUC = 0.88 in the NAcc, AUC = 0.94 in the PFC). In order to capture the alcohol effect on the mitochondrial DNA methylation, we reassigned the 53 deceased individuals into the BAC-negative group (with undetected blood alcohol concentration, n = 34), the Alcohol group (with ante-mortem alcohol use, n = 10) and the Fermentation group (with the detected blood alcohol from bacterial fermentation, n = 9). Finally, we summarized the transient effect of alcohol use on the methylation, which could significantly differentiate the ante-mortem alcohol users from the non-users (AUC = 0.89 in the NAcc, AUC = 0.94 in the PFC). The mitochondrial global hypomethylation, reflecting the chronic effect of the alcohol use, was selectively observed in the NAcc due to the different resiliencies of the two brain areas. Conclusion: The mitochondrial methylations were different between different brain areas, generally accumulated with aging, and sensitive to the effects of illicit drugs and alcohol. We believed this is the first report to elucidate comprehensively the importance of mitochondrial DNA methylation in human brain. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90817 |
DOI: | 10.6342/NTU202301330 |
全文授權: | 未授權 |
顯示於系所單位: | 流行病學與預防醫學研究所 |
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