Ethanol induced acetylation of histone at G9a exon1 and G9a-mediated histone H3 dimethylation leads to neurodegeneration in neonatal mice.
Ethanol induced acetylation of histone at G9a exon1 and G9a-mediated histone H3 dimethylation leads to neurodegeneration in neonatal mice.
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DOI：
10.1016/j.neuroscience.2013.11.043
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发表时间：
2014-01-31
期刊：
影响因子：
3.3
通讯作者：
Basavarajappa BS
中科院分区：
文献类型：
--
作者：
Subbanna S;Nagre NN;Shivakumar M;Umapathy NS;Psychoyos D;Basavarajappa BS
未成熟啮齿动物在出生后第7天（P7）短暂暴露于乙醇，与人类妊娠晚期的时间点相当，诱导神经变性。然而，乙醇对发育中的大脑有害影响的分子机制知之甚少。在我们之前的研究中，我们表明在P7处给予高剂量乙醇会增强G9 a，并导致半胱天冬酶-3介导的赖氨酸9（H3 K9 me2）上二甲基化H3的降解。在这项研究中，我们调查了在G9a外显子1，G9a介导的H3二甲基化神经变性和G9a相关蛋白在P7脑暴露于低剂量乙醇后的表观遗传变化的潜在作用。我们发现，低剂量乙醇诱导P7小鼠轻度神经退行性变，在G9a外显子1和G9a蛋白水平上增强H3赖氨酸14（H3K14ace）的特异性乙酰化，增强H3K9和H3赖氨酸27（H3K27me2）的二甲基化。然而，二甲基化的H3K9和K27均未发生降解。乙醇处理前G9a活性的药理学抑制防止了H3二甲基化和神经变性。此外，我们的免疫沉淀数据表明，G9a直接与DNA甲基转移酶（DNMT3A）和甲基CpG结合蛋白2（MeCP2）。此外，DNMT3A和MeCP2蛋白水平通过低剂量的乙醇增强，其显示出诱导轻度神经变性。总的来说，这些表观遗传改变导致G9a、DNMT3A和MeCP 2的结合以形成更大的抑制复合物，并且在发育中的大脑中的低剂量乙醇诱导的神经变性中具有显著作用。
The transient exposure of immature rodents to ethanol during postnatal day 7 (P7), comparable to a time point within the third trimester of human pregnancy, induces neurodegeneration. However, the molecular mechanisms underlying the deleterious effects of ethanol on the developing brain are poorly understood. In our previous study, we showed that a high dose administration of ethanol at P7 enhances G9a and leads to caspase-3-mediated degradation of dimethylated H3 on lysine 9 (H3K9me2). In this study, we investigated the potential role of epigenetic changes at G9a exon1, G9a-mediated H3 dimethylation on neurodegeneration and G9a-associated proteins in the P7 brain following exposure to a low dose of ethanol. We found that a low dose of ethanol induces mild neurodegeneration in P7 mice, enhances specific acetylation of H3 on lysine 14 (H3K14ace) at G9a exon1, G9a protein levels, augments the dimethylation of H3K9 and H3 lysine 27 (H3K27me2). However, neither dimethylated H3K9 nor K27 underwent degradation. Pharmacological inhibition of G9a activity prior to ethanol treatment prevented H3 dimethylation and neurodegeneration. Further, our immunoprecipitation data suggest that G9a directly associates with DNA methyltransferase (DNMT3A) and methyl-CpG-binding protein 2 (MeCP2). In addition, DNMT3A and MeCP2 protein levels were enhanced by a low dose of ethanol that was shown to induce mild neurodegeneration. Collectively, these epigenetic alterations lead to association of G9a, DNMT3A and MeCP2 to form a larger repressive complex and have a significant role in low dose ethanol-induced neurodegeneration in the developing brain.