GenomeEast Platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/University of Strasbourg-UMR 7104, 1 rue Laurent Fries, 67404 Illkirch, France.
University of Strasbourg, Laboratory of Cognitive and Adaptive Neurosciences (LNCA), 12 rue Goethe, 67000 Strasbourg, France.
Sci Rep. 2017 Feb 22;7:42875. doi: 10.1038/srep42875.
Epigenetic and transcriptional alterations are both implicated in Huntington's disease (HD), a progressive neurodegenerative disease resulting in degeneration of striatal neurons in the brain. However, how impaired epigenetic regulation leads to transcriptional dysregulation in HD is unclear. Here, we investigated enhancer RNAs (eRNAs), a class of long non-coding RNAs transcribed from active enhancers. We found that eRNAs are expressed from many enhancers of mouse striatum and showed that a subset of those eRNAs are deregulated in HD vs control mouse striatum. Enhancer regions producing eRNAs decreased in HD mouse striatum were associated with genes involved in striatal neuron identity. Consistently, they were enriched in striatal super-enhancers. Moreover, decreased eRNA expression in HD mouse striatum correlated with down-regulation of associated genes. Additionally, a significant number of RNA Polymerase II (RNAPII) binding sites were lost within enhancers associated with decreased eRNAs in HD vs control mouse striatum. Together, this indicates that loss of RNAPII at HD mouse enhancers contributes to reduced transcription of eRNAs, resulting in down-regulation of target genes. Thus, our data support the view that eRNA dysregulation in HD striatum is a key mechanism leading to altered transcription of striatal neuron identity genes, through reduced recruitment of RNAPII at super-enhancers.
表观遗传和转录改变都与亨廷顿病（HD）有关，这是一种进行性神经退行性疾病，导致大脑纹状体神经元的退化。然而，表观遗传调控的损伤如何导致 HD 中的转录失调尚不清楚。在这里，我们研究了增强子 RNA（eRNA），这是一类从活性增强子转录的长非编码 RNA。我们发现 eRNA 是从小鼠纹状体的许多增强子中表达的，并且发现与对照小鼠纹状体相比，这些 eRNA 中有一部分在 HD 中失调。在 HD 小鼠纹状体中产生 eRNA 的增强子区域与参与纹状体神经元身份的基因有关。一致地，它们在纹状体超级增强子中富集。此外，HD 小鼠纹状体中 eRNA 表达的减少与相关基因的下调相关。此外，在与 HD 对照小鼠纹状体中减少的 eRNA 相关的增强子中，大量 RNA 聚合酶 II（RNAPII）结合位点丢失。总的来说，这表明 HD 小鼠增强子中 RNAPII 的丢失导致 eRNA 转录减少，从而导致靶基因下调。因此，我们的数据支持这样一种观点，即 HD 纹状体中 eRNA 的失调是通过超级增强子中 RNAPII 的募集减少导致纹状体神经元身份基因转录改变的关键机制。
