CB1-receptor knockout neonatal mice are protected against ethanol-induced impairments of DNMT1, DNMT3A, and DNA methylation.
CB1-receptor knockout neonatal mice are protected against ethanol-induced impairments of DNMT1, DNMT3A, and DNA methylation.
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DOI：
10.1111/jnc.13006
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发表时间：
2015-02
影响因子：
4.7
通讯作者：
Basavarajappa BS
中科院分区：
文献类型：
--
作者：
Nagre NN;Subbanna S;Shivakumar M;Psychoyos D;Basavarajappa BS
妊娠期间使用乙醇的显著后果是神经行为异常，涉及海马和新皮质功能障碍，导致学习和记忆缺陷，统称为胎儿酒精谱系障碍（FASD）。然而，这些异常的分子机制仍然知之甚少，因此需要系统的研究。在这里，我们在FASD小鼠模型中记录了新的表观遗传异常。乙醇处理P7小鼠，诱导caspase-3的活化，通过降低DNA甲基转移酶（DNMT 1和DNMT 3A）水平损害DNA甲基化。在乙醇处理之前抑制caspase-3活性，拯救了DNMT 1、DNMT 3A蛋白以及DNA甲基化水平。在乙醇处理之前，阻断组蛋白甲基转移酶（G9 a）活性或大麻素受体1型（CB 1 R），分别抑制或阻止caspase-3的活化，挽救了DNMT 1和DNMT 3A蛋白和DNA甲基化。在P7 CB 1 R敲除小鼠中未发现DNMT 1和DNMT 3A蛋白和DNA甲基化的减少，其未表现出乙醇诱导的caspase-3活化。总之，这些数据表明，乙醇诱导的半胱天冬酶-3激活损害DNA甲基化通过DNMT 1和DNMT 3A在新生小鼠脑，这种损害是不存在的CB 1 R null小鼠。DNA甲基化介导的表观遗传事件可能是乙醇致畸的重要机制之一。
The significant consequences of ethanol use during pregnancy are neurobehavioral abnormalities involving hippocampal and neocortex malfunctions that cause learning and memory deficits collectively named fetal alcohol spectrum disorder (FASD). However, the molecular mechanisms underlying these abnormalities are still poorly understood and therefore warrant systematic research. Here, we document novel epigenetic abnormalities in the mouse model of FASD. Ethanol treatment of P7 mice, which induces activation of caspase-3, impaired DNA methylation through reduced DNA methyltransferases (DNMT1 and DNMT3A) levels. Inhibition of caspase-3 activity, before ethanol treatment, rescued DNMT1, DNMT3A proteins as well as DNA methylation levels. Blockade of histone methyltransferase (G9a) activity or cannabinoid receptor type-1 (CB1R), prior to ethanol treatment, which respectively inhibits or prevents activation of caspase-3, rescued the DNMT1 and DNMT3A proteins and DNA methylation. No reduction of DNMT1 and DNMT3A proteins and DNA methylation was found in P7 CB1R null mice, which exhibit no ethanol-induced activation of caspase-3. Together, these data demonstrate that ethanol-induced activation of caspase-3 impairs DNA methylation through DNMT1 and DNMT3A in the neonatal mouse brain, and such impairments are absent in CB1R null mice. Epigenetic events mediated by DNA methylation may be one of the essential mechanisms of ethanol teratogenesis.
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产前酒精暴露后小鼠 Igf2 基因座 DNA 甲基化和基因表达略有下降：甲基补充饮食的影响。
影响因子：
2.3
作者：
Downing, Chris;Johnson, Thomas E.;Larson, Colin;Leakey, Tatiana I.;Siegfried, Rachel N.;Rafferty, Tonya M.;Cooney, Craig A.
通讯作者：
Cooney, Craig A.
DOI：
10.1073/pnas.93.22.12406
发表时间：
1996-10-29
影响因子：
11.1
作者：
Kakutani, T;Jeddeloh, JA;Richards, EJ
通讯作者：
Richards, EJ
Dnmt1 和 Dnmt3a 维持 DNA 甲基化并调节成人前脑神经元的突触功能
影响因子：
25
作者：
Feng, Jian;Zhou, Yu;Campbell, Susan L.;Le, Thuc;Li, En;Sweatt, J. David;Silva, Alcino J.;Fan, Guoping
通讯作者：
Fan, Guoping
影响因子：
5.3
作者：
Biniszkiewicz, D;Gribnau, J;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
8
作者：
Clark, CM;Li, D;Loock, C
通讯作者：
Loock, C