Male germline transmits fetal alcohol adverse effect on hypothalamic proopiomelanocortin gene across generations.
Male germline transmits fetal alcohol adverse effect on hypothalamic proopiomelanocortin gene across generations.
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DOI：
10.1016/j.biopsych.2012.04.006
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发表时间：
2012-09-01
影响因子：
10.6
通讯作者：
Sarkar, Dipak K.
中科院分区：
文献类型：
--
作者：
Govorko, Dmitry;Bekdash, Rola A.;Zhang, Changqing;Sarkar, Dipak K.
关键词：
含有proopiomelanocortin （POMC）衍生肽的神经元，已知控制应激轴、代谢和免疫功能，但在有酗酒家族史的患者中功能较低，这提高了酒精对POMC系统的影响可能代代相传的可能性。在这里，我们描述了Pomc基因的表观遗传修饰，通过男性生殖系代代传递，并可能在酒精遗传疾病中起关键作用。通过测定Pomc基因甲基化、表达和功能异常及其在DNA甲基化或组蛋白乙酰化抑制后的正常化，研究胎儿酒精暴露大鼠Pomc表达缺陷是否涉及表观遗传机制。此外，还进行了跨代研究，以评估酒精的种系传播效应。胎儿酒精暴露的雄性和雌性大鼠后代显示出POMC神经元功能的显著缺陷。与此相关的是Pomc启动子区域近端CpG二核苷酸甲基化状态的增加，以及Pomc神经元中组蛋白修饰蛋白和DNA甲基转移酶水平的改变。抑制组蛋白去乙酰化和DNA甲基化使Pomc表达和功能异常正常化。胎儿酒精诱导的Pomc基因甲基化、表达和功能缺陷在F2和F3雄性中持续存在，而在雌性种系中不存在。此外，在胎儿酒精暴露F1后代的精子中检测到高甲基化的Pomc基因，这些后代通过雄性种系通过F3代传播。跨代表观遗传学研究应该激发对影响酒精遗传疾病遗传风险性别依赖差异的生物学机制的新见解。
Neurons containing proopiomelanocortin (POMC) derived peptides, known to control stress axis, metabolic and immune functions, have a lower function in patients with a family history of alcoholism, raising the possibility that alcohol effects on the POMC system may transmit through generations. Here we describe epigenetic modifications of Pomc gene that transmit through generation via male germline and may be critically involved in alcoholism-inherited diseases. Whether an epigenetic mechanism is involved in causing a Pomc expression deficit in fetal alcohol exposed rats is studied by determining Pomc gene methylation, expression and functional abnormalities and their normalization following suppression of DNA methylation or histone acetylation. Additionally, transgenerational studies were conducted to evaluate the germline-transmitted effect of alcohol. Fetal alcohol exposed male and female rat offspring showed a significant deficit in POMC neuronal functions. Associated with this was an increased methylation status of several CpG dinucleotides in the proximal part of the Pomc promoter region and altered level of histone modifying proteins and DNA methyltransferases levels in POMC neurons. Suppression of histone deacetylation and DNA methylation normalized Pomc expression and functional abnormalities. Fetal alcohol-induced Pomc gene methylation, expression and functional defects persisted in the F2 and F3 male but not in female germline. Additionally, the hypermethylated Pomc gene was detected in sperms of fetal alcohol exposed F1 offspring that was transmitted through F3 generation via male germline. Trangenerational epigenetic studies should spur new insight into the biological mechanisms that influence the sex-dependent difference in genetic risk of alcoholism-inherited diseases.
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影响因子：
64.5
作者：
Carone BR;Fauquier L;Habib N;Shea JM;Hart CE;Li R;Bock C;Li C;Gu H;Zamore PD;Meissner A;Weng Z;Hofmann HA;Friedman N;Rando OJ
通讯作者：
Rando OJ
影响因子：
10.6
作者：
Hernandez-Avila, CA;Oncken, C;Kranzler, HR
通讯作者：
Kranzler, HR
DOI：
10.1007/978-1-60327-389-3_22
发表时间：
2010-01-01
期刊：
RAT GENOMICS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Kashiwazaki, Naomi;Seita, Yasunari;Serikawa, Tadao
通讯作者：
Serikawa, Tadao
影响因子：
3.3
作者：
Kelley, Michelle L.;Braitman, Abby;Gumienny, Leslie
通讯作者：
Gumienny, Leslie
影响因子：
8.8
作者：
LISSONI, P;BARNI, S;TANCINI, G
通讯作者：
TANCINI, G