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.
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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BAF（BRG1/BRM相关因子）染色质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编码基因基因座的转录。
DOI：
10.1016/j.alcohol.2017.01.003
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Miranda RC
中科院分区：
文献类型：
--
作者：
Burrowes SG;Salem NA;Tseng AM;Balaraman S;Pinson MR;Garcia C;Miranda RC
胎儿酒精谱系障碍是全球智力残疾的主要原因。先前的研究表明，发育中的乙醇暴露导致包括miR-9在内的microRNA（miRNA）的丢失，而这些miRNA的丢失反过来又介导了乙醇在发育中的大脑中的一些致畸作用。我们先前发现，乙醇增加了小鼠胎儿神经干细胞（NSC）中miR-9-2编码基因位点的甲基化，推进了该位点的表观遗传沉默机制，从而导致NSC中miR-9的丢失。因此，我们评估了BAF（BRG 1/BRM相关因子）复合物作为乙醇对miR-9影响的表观遗传介质的作用，该复合物分解核小体以促进染色质的进入。染色质免疫沉淀和DNAse-I超敏反应分析表明，BAF复合物与miR-9-2基因座的转录可及区域和异染色质区域相关，并且通过BAF 170和BAF 155的联合敲除使BAF复合物解体导致miR-9显著减少。我们假设乙醇暴露会导致miR-9-2位点BAF复合物功能的丧失。然而，乙醇暴露显着增加mRNA转录成熟相关的BAF复合体成员，BAF 170，SS 18，ARID 2，BAF 60 a，BRM/BAF 190 b和BAF 53 b。乙醇还显著增加了含有CpG岛的内含子内和末端外显子编码前体（前）-miR-9-2中的BAF复合物结合。这些数据表明，BAF复合物可以适应性地响应于乙醇暴露，以防止胎儿NSC中miR-9-2的完全丢失。染色质重塑因子可以适应致畸剂的存在，以维持关键的miRNA调控途径的转录。
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.
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