Repeated vapor ethanol exposure induces transient histone modifications in the brain that are modified by genotype and brain region.
Repeated vapor ethanol exposure induces transient histone modifications in the brain that are modified by genotype and brain region.
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DOI：
10.3389/fnmol.2015.00039
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发表时间：
2015
影响因子：
4.8
通讯作者：
Homanics GE
中科院分区：
文献类型：
--
作者：
Finegersh A;Ferguson C;Maxwell S;Mazariegos D;Farrell D;Homanics GE
背景：新兴研究表明乙醇（EtOH）诱导的表观遗传修饰在调节基因表达和EtOH消耗中起作用。然而，关于EtOH诱导的特异性表观遗传修饰尚未达成共识，这使得确定机制和开发靶向治疗具有挑战性。我们假设慢性间歇性EtOH （CIE）诱导大脑皮层（CCx）、伏隔核（NAc）和前额叶皮层（PFC）的组蛋白修饰持续变化，并且这些组蛋白修饰在敲入小鼠品系中发生改变，对EtOH的敏感性发生改变。方法：以B6为背景的C57BL/6J （B6）小鼠和α1SHLA敲入小鼠连续4 d暴露于16 h的蒸汽乙醚或8 h的室内空气中，并在暴露后72 h的多个时间点进行处死。Western blot和dot blot检测组蛋白修饰。结果：在NAc中，CIE显著增加了赖氨酸9 （H3K9ac）位点组蛋白亚基H3的乙酰化，而赖氨酸14 （H3K14ac）和赖氨酸27 （H3K27ac）位点组蛋白亚基H3的乙酰化。在PFC中，CIE显著提高了H3K9ac，但没有提高H3K14或H3K27ac。在暴露于EtOH后8或72 h， NAc或pfc中没有明显变化。CIE也与NAc中Kat2b、Kat5和Tet1的表达增加有关，但与pfc无关。在CCx中，CIE对H3K18ac水平有显著影响；α1SHLA突变对H3K27me3、H3K14ac和H3K18ac水平也有显著影响，对H3S10pK14ac也有影响。结论：etoh诱导的组蛋白修饰是短暂的，且在脑区之间存在显著差异。一种基因突变改变了对EtOH的敏感性，与CIE期间组蛋白修饰的诱导改变有关。这些结果对研究EtOH诱导的组蛋白修饰和EtOH敏感性具有重要意义。
Background: Emerging research implicates ethanol (EtOH)-induced epigenetic modifications in regulating gene expression and EtOH consumption. However, consensus on specific epigenetic modifications induced by EtOH has not yet emerged, making it challenging to identify mechanisms and develop targeted treatments. We hypothesized that chronic intermittent EtOH (CIE) induces persistent changes in histone modifications across the cerebral cortex (CCx), nucleus accumbens (NAc), and prefrontal cortex (PFC), and that these histone modifications are altered in a knock-in mouse strain with altered sensitivity to EtOH. Methods: C57BL/6J (B6) mice and α1SHLA knockin mice on a B6 background were exposed to 16 h of vapor EtOH or room air followed by 8 h of room air for 4 consecutive days and sacrificed at multiple time points up to 72 h following exposure. Histone modifications were assessed using Western blot and dot blot. RT-qPCR was used to study expression of chromatin modifying enzymes in NAc and PFC. Results: In NAc, CIE significantly increased acetylation of histone subunit H3 at lysine 9 (H3K9ac) but not lysine 14 (H3K14ac) or lysine 27 (H3K27ac). In PFC, CIE significantly increased H3K9ac but not H3K14 or H3K27ac. There were no significant changes at 8 or 72 h after EtOH exposure in either NAc or PFC. CIE was also associated with increased expression of Kat2b, Kat5, and Tet1 in NAc but not PFC. In CCx, CIE had a significant effect on levels of H3K18ac; there was also a significant effect of the α1SHLA mutation on levels of H3K27me3, H3K14ac, and H3K18ac as well as a trend for H3S10pK14ac. Conclusions: The EtOH-induced histone modifications observed were transient and varied significantly between brain regions. A genetic mutation that altered sensitivity to EtOH was associated with altered induction of histone modifications during CIE. These results have implications for studying EtOH-induced histone modifications and EtOH sensitivity.