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首页> 外文期刊>Alcohol >The BAF (BRG1/BRM-Associated Factor) chromatin-remodeling complex exhibits ethanol sensitivity in fetal neural progenitor cells and regulates transcription at the miR-9-2 encoding gene locus
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The BAF (BRG1/BRM-Associated Factor) chromatin-remodeling complex exhibits ethanol sensitivity in fetal neural progenitor cells and regulates transcription at the miR-9-2 encoding gene locus

机译：BAF（BRG1 / BRM相关因子）染色质重塑复合物在胎儿神经祖细胞中表现出乙醇敏感性，并调节MIR-9-2编码基因座的转录

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Fetal alcohol spectrum disorders are a leading cause of intellectual disability worldwide. Previous studies have shown that developmental ethanol exposure results in loss of microRNAs (miRNAs), including miR-9, and loss of these miRNAs, in turn, mediates some of ethanol's teratogenic effects in the developing brain. We previously found that ethanol increased methylation at the miR-9-2 encoding gene locus in mouse fetal neural stem cells (NSC), advancing a mechanism for epigenetic silencing of this locus and consequently, miR-9 loss in NSCs. Therefore, we assessed the role of the BAF (BRG1/BRM-Associated Factor) complex, which disassembles nucleosomes to facilitate access to chromatin, as an epigenetic mediator of ethanol's effects on miR-9. Chromatin immunoprecipitation and DNAse I-hypersensitivity analyses showed that the BAF complex was associated with both transcriptionally accessible and heterochromatic regions of the miR-9-2 locus, and that disintegration of the BAF complex by combined knockdown of BAF170 and BAF155 resulted in a significant decrease in miR-9. We hypothesized that ethanol exposure would result in loss of BAF-complex function at the miR-9-2 locus. However, ethanol exposure significantly increased mRNA transcripts for maturation-associated BAF-complex members BAF170, SS18, ARID2, BAF60a, BRM/BAF190b, and BAF53b. Ethanol also significantly increased BAF-complex binding within an intron containing a CpG island and in the terminal exon encoding precursor (pre)-miR-9-2. These data suggest that the BAF complex may adaptively respond to ethanol exposure to protect against a complete loss of miR-9-2 in fetal NSCs. Chromatin remodeling factors may adapt to the presence of a teratogen, to maintain transcription of critical miRNA regulatory pathways. (C) 2017 Elsevier Inc. All rights reserved.
机译：胎儿酒精谱紊乱是全世界知识分子残疾的主要原因。之前的研究表明，发育乙醇暴露导致MicroRNA（miRNA）的丧失，包括miR-9，以及这些miRNA的丧失，反过来介导一些乙醇在显影大脑中的致畸作用。我们之前发现乙醇在小鼠胎儿神经干细胞（NSC）中编码基因座的miR-9-2中的甲基化，推进了该基因座的表观遗传沉默机制，因此，NSCs中的miR-9损失。因此，我们评估了BAF（BRG1 / BRM相关因子）复合物的作用，该作用拆解核心以促进染色质的促进染色体，作为乙醇对miR-9的影响的表观遗传介质。染色质免疫沉淀和DNA酶I-超敏反应分析表明，BAF络合物与miR-9-2基因座的转录可接近和异色区有关，并且通过BAF170和BAF155的组合敲低的BAF复合物的崩解导致显着降低在miR-9。我们假设乙醇暴露会导致MIR-9-2基因座的BAF复杂功能丧失。然而，乙醇暴露显着增加了成熟的BAF-复合成员BAF170，SS18，ARID2，BAF60A，BRM / BAF190B和BAF53B的MRNA转录物。乙醇在含有CPG岛和末端外显子性前体（PRE）-MIR-9-2的内部外显子中，乙醇也显着增加了BAF复合物结合。这些数据表明，BAF复合物可以自适应地响应乙醇暴露，以防止胎儿NSC中的miR-9-2的完全丧失。染色质重塑因子可能适应致畸性的存在，维持关键miRNA调节途径的转录。 （c）2017年Elsevier Inc.保留所有权利。

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