Acute ethanol alters multiple histone modifications at model gene promoters in the cerebral cortex.
Acute ethanol alters multiple histone modifications at model gene promoters in the cerebral cortex.
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DOI：
10.1111/acer.12465
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Homanics GE
中科院分区：
文献类型：
--
作者：
Finegersh A;Homanics GE
乙醇 (EtOH) 暴露会改变大脑皮层 (CCx) 的基因表达；然而，乙醇诱导的基因调控机制尚不清楚。我们假设 EtOH 通过差异改变基因启动子上的组蛋白修饰来调节基因表达，而基因启动子上的组蛋白修饰被 EtOH 上调和下调。这种表观遗传机制可能最终导致乙醇诱导的神经适应，而神经适应是耐受性、依赖性和乙醇使用障碍的基础。用 3 g/kg EtOH（腹腔注射）或盐水处理八周龄雄性 C57BL/6J 小鼠，并在注射后 6 小时处死；立即取出 CCx 和海马 (HC) 并快速冷冻。染色质免疫沉淀 (ChIP) 用于研究模型基因启动子与组蛋白修饰的关联。蛋白质印迹用于检测所研究的组蛋白修饰的整体变化。我们还使用 PCR 阵列来识别染色质修饰酶表达的变化。在 CCx 中，急性 EtOH 降低了 Gad1、Hdac2 和 Hdac11 的表达，这与 Gad1 和 Hdac2 启动子处的组蛋白乙酰化降低有关；我们还发现 Mt1、Mt2、Egr1 表达增加，这与 Mt2 启动子处 H3K4me3 水平增加和 Mt1 启动子处 H3K27me3 水平减少有关。我们发现 CCx 中 H3K4me3 的整体水平有所增加，HC 中 H3K9ac 和 H3K14ac 的整体水平有所增加。 PCR 阵列发现 CCx 中 Csrp2bp、Hdac2 和 Hdac11 的表达减少，而 Kat2b 的表达增加。急性 EtOH 会诱导 CCx 模型上调和下调基因的染色质重塑。这些基因启动子处的组蛋白修饰的不同模式表明，EtOH 可能通过多种组蛋白修饰酶来改变基因表达。特别是，CCx 中 Kat2b、Hdac2、Hdac11 和 Csrp2bp 的差异表达可能介导 EtOH 诱导的染色质重塑。需要进行更多研究来确定乙醇诱导的组蛋白修饰酶变化、特定的乙醇诱导的组蛋白修饰和基因表达之间的关系。
Ethanol (EtOH) exposure alters gene expression in the cerebral cortex (CCx); however, mechanisms of EtOH-induced gene regulation are not well understood. We hypothesized that EtOH regulates gene expression by differentially altering histone modifications at gene promoters that are up- and down-regulated by EtOH. Such epigenetic mechanisms may ultimately contribute to EtOH-induced neuro-adaptations that underlie tolerance, dependence, and EtOH use disorders. Eight-week-old, male C57BL/6J mice were treated with 3 g/kg EtOH (i.p.) or saline and sacrificed 6 hours after injection; the CCx and hippocampus (HC) were immediately removed and flash frozen. Chromatin immunoprecipitation (ChIP) was used to study the association of model gene promoters with histone modifications. Western blot was used to detect global changes in the histone modifications studied. We also used a PCR array was used to identify changes in expression of chromatin modifying enzymes. In CCx, acute EtOH decreased expression of Gad1, Hdac2, and Hdac11, which was associated with decreased histone acetylation at the Gad1 and Hdac2 promoters; we also identified increased expression of Mt1, Mt2, Egr1, which was associated with increased H3K4me3 levels at the Mt2 promoter and decreased H3K27me3 levels at the Mt1 promoter. We identified an increase in global levels of H3K4me3 in CCx as well as a global increase in H3K9ac and H3K14ac in HC. The PCR array identified decreased expression of Csrp2bp, Hdac2, and Hdac11 as well as increased expression of Kat2b in CCx. Acute EtOH induces chromatin remodeling at model up- and down-regulated genes in CCx. Different patterns of histone modifications at these gene promoters indicate that EtOH may be acting through multiple histone modifying enzymes to alter gene expression; in particular, differential expression of Kat2b, Hdac2, Hdac11, and Csrp2bp in CCx may mediate EtOH-induced chromatin remodeling. Additional studies are necessary to determine the relationship between EtOH-induced changes in histone modifying enzymes, specific EtOH-induced histone modifications, and gene expression.
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DOI：
10.1523/jneurosci.3136-11.2012
发表时间：
2012-02-01
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ponomarev I;Wang S;Zhang L;Harris RA;Mayfield RD
通讯作者：
Mayfield RD
影响因子：
4.7
作者：
Pascual, Maria;Do Couto, Bruno R.;Guerri, Consuelo
通讯作者：
Guerri, Consuelo
影响因子：
34.7
作者：
Robison, Alfred J.;Nestler, Eric J.
通讯作者：
Nestler, Eric J.
影响因子：
21.3
作者：
Schneider, R;Bannister, AJ;Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
56.9
作者：
NESTOROS, JN
通讯作者：
NESTOROS, JN