Adolescent binge ethanol impacts H3K36me3 regulation of synaptic genes.
Adolescent binge ethanol impacts H3K36me3 regulation of synaptic genes.
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DOI：
10.3389/fnmol.2023.1082104
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发表时间：
2023
影响因子：
4.8
通讯作者：
Wolstenholme, Jennifer T.
中科院分区：
文献类型：
--
作者：
Brocato, Emily R.;Wolstenholme, Jennifer T.
青春期的部分标志是前额叶皮层（PFC）的持续发育。在神经发育的这一关键阶段，酒精的过度使用会导致PFC发生重大的结构变化，以及可能持续到成年期的认知和行为缺陷。先前的研究表明，青少年酗酒导致工作记忆的持久缺陷，负责组蛋白3赖氨酸36（H3 K36）甲基化的染色质重塑基因的表达减少，以及PFC中H3 K36的整体减少。H3 K36 me 3存在于活跃转录基因的编码区中，并通过RNA聚合酶II保护异常的隐蔽转录。我们推测H3 K36的甲基化改变可能在青少年酗酒引起的记忆障碍中发挥作用。为了在分子水平上研究这一点，将乙醇（4g/kg，i.g.）或水间歇地给予青春期小鼠。然后在同一组织内进行RNA和ChIP测序以确定基因表达变化并鉴定其中H3 K36 me 3被乙醇破坏的基因和位点。我们进一步评估了乙醇诱导的变化，在转录水平与差异外显子使用和隐蔽的转录分析-一个标志，减少H3 K36 me 3。在这里，我们发现乙醇诱导的基因表达的变化和H3 K36 me 3-调节突触相关基因在我们所有的分析。值得注意的是，H3 K36 me 3在乙醇和对照条件下在突触相关基因上发生了差异性三甲基化，Snap 25和Cplx 1在青春期用乙醇处理的男性和女性中显示出隐蔽转录的证据。我们的研究结果提供了初步的证据，乙醇诱导的变化，在青少年神经发育过程中H3 K36 me 3可能与突触失调在转录水平，这可能解释了乙醇诱导的变化PFC突触功能。
Adolescence is marked in part by the ongoing development of the prefrontal cortex (PFC). Binge ethanol use during this critical stage in neurodevelopment induces significant structural changes to the PFC, as well as cognitive and behavioral deficits that can last into adulthood. Previous studies showed that adolescent binge ethanol causes lasting deficits in working memory, decreases in the expression of chromatin remodeling genes responsible for the methylation of histone 3 lysine 36 (H3K36), and global decreases in H3K36 in the PFC. H3K36me3 is present within the coding region of actively-transcribed genes, and safeguards against aberrant, cryptic transcription by RNA Polymerase II. We hypothesize that altered methylation of H3K36 could play a role in adolescent binge ethanol-induced memory deficits. To investigate this at the molecular level, ethanol (4 g/kg, i.g.) or water was administered intermittently to adolescent mice. RNA-and ChIP-sequencing were then performed within the same tissue to determine gene expression changes and identify genes and loci where H3K36me3 was disrupted by ethanol. We further assessed ethanol-induced changes at the transcription level with differential exon-use and cryptic transcription analysis – a hallmark of decreased H3K36me3. Here, we found ethanol-induced changes to the gene expression and H3K36me3-regulation of synaptic-related genes in all our analyses. Notably, H3K36me3 was differentially trimethylated between ethanol and control conditions at synaptic-related genes, and Snap25 and Cplx1 showed evidence of cryptic transcription in males and females treated with ethanol during adolescence. Our results provide preliminary evidence that ethanol-induced changes to H3K36me3 during adolescent neurodevelopment may be linked to synaptic dysregulation at the transcriptional level, which may explain the reported ethanol-induced changes to PFC synaptic function.
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DOI：
10.1111/j.1530-0277.2010.01385.x
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期刊：
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影响因子：
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影响因子：
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作者：
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影响因子：
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