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首页> 外文期刊>Epigenetics & Chromatin >Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription
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Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription

机译：通过妊娠酒精暴露的抗氧化磷酸化和线粒体功能的编程抑制与不抑制转录的H3K9ME2的普遍增加相关

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A critical question emerging in the field of developmental toxicology is whether alterations in chromatin structure induced by toxicant exposure control patterns of gene expression or, instead, are structural changes that are part of a nuclear stress response. Previously, we used a mouse model to conduct a three-way comparison between control offspring, alcohol-exposed but phenotypically normal animals, and alcohol-exposed offspring exhibiting craniofacial and central nervous system structural defects. In the cerebral cortex of animals exhibiting alcohol-induced dysgenesis, we identified a dramatic increase in the enrichment of dimethylated histone H3, lysine 9 (H3K9me2) within the regulatory regions of key developmental factors driving histogenesis in the brain. However, whether this change in chromatin structure is causally involved in the development of structural defects remains unknown. Deep-sequencing analysis of the cortex transcriptome reveals that the emergence of alcohol-induced structural defects correlates with disruptions in the genetic pathways controlling oxidative phosphorylation and mitochondrial function. The majority of the affected pathways are downstream targets of the mammalian target of rapamycin complex 2 (mTORC2), indicating that this stress-responsive complex plays a role in propagating the epigenetic memory of alcohol exposure through gestation. Importantly, transcriptional disruptions of the pathways regulating oxidative homeostasis correlate with the emergence of increased H3K9me2 across genic, repetitive, and non-transcribed regions of the genome. However, although associated with gene silencing, none of the candidate genes displaying increased H3K9me2 become transcriptionally repressed, nor do they exhibit increased markers of canonical heterochromatin. Similar to studies in C. elegans, disruptions in oxidative homeostasis induce the chromatin looping factor SATB2, but in mammals, this protein does not appear to drive increased H3K9me2 or altered patterns of gene expression. Our studies demonstrate that changes in H3K9me2 associate with alcohol-induced congenital defects, but that this epigenetic change does not correlate with transcriptional suppression. We speculate that the mobilization of SATB2 and increased enrichment of H3K9me2 may be components of a nuclear stress response that preserve chromatin integrity and interactions under prolonged oxidative stress. Further, we postulate that while this response may stabilize chromatin structure, it compromises the nuclear plasticity required for normal differentiation.
机译：在发育毒理学领域出现的关键问题是由基因表达的毒物暴露对照模式诱导的染色质结构的变化是核应激反应的一部分的结构变化。以前，我们使用了小鼠模型来进行控制后代，醇暴露但表型正常动物之间的三向比较，以及含酒精的后代表现出颅面和中枢神经系统结构缺陷。在表现出酒精诱导的饮食性的动物的脑皮质中，我们确定了在脑部中促进脑中组织发生的关键发育因子的调节区域内富集的二甲基化组蛋白H3，赖氨酸9（H3K9ME2）的富集。然而，染色质结构的这种变化是否有因果涉及结构缺陷的发展仍然未知。皮质转录组的深序分析表明，酒精诱导的结构缺陷的出现与控制氧化磷酸化和线粒体功能的遗传途径中断相关。大多数受影响的途径是哺乳动物催乳素复合物2（MTORC2）的哺乳动物靶标的下游靶标，表明这种应激响应性复合物在通过妊娠通过妊娠传播酒精暴露的表观遗传记忆中起作用。重要的是，调节氧化稳态的途径的转录破坏与基因组的基因，重复和非转录区域增加的H3K9ME2的出现相关。然而，尽管与基因沉默相关，但显示出增加的H3K9ME2的候选基因没有任何候选基因变得转录压抑，但它们也没有表现出典型的异铬胺的增加的标记。类似于C.杆状杆菌的研究，氧化稳态的破坏诱导染色质循环因子SATB2，但在哺乳动物中，该蛋白质不会促进增加的H3K9ME2或改变基因表达模式。我们的研究表明，H3K9ME2的变化与酒精诱导的先天性缺陷相关，但这种表观遗传变化与转录抑制不相关。我们推测SATB2的动员和H3K9ME2的增加的富集可以是核应力反应的组分，其保持染色蛋白完整性和延长氧化应激的相互作用。此外，我们假设这一点虽然这种反应可以稳定染色质结构，但它会损害正常分化所需的核可塑性。

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