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Sci Rep. 2017 Feb 22;7:42875. doi: 10.1038/srep42875.

Altered enhancer transcription underlies Huntington's disease striatal transcriptional signature.

Author information

1
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.
2
University of Strasbourg, Laboratory of Cognitive and Adaptive Neurosciences (LNCA), 12 rue Goethe, 67000 Strasbourg, France.
3
CNRS, LNCA UMR 7364, 12 rue Goethe, 67000 Strasbourg, France.
4
Commissariat à l'Energie Atomique (CEA), Département de Recherches Fondamentales (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France.
5
Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.

Abstract

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.

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