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Hum Mol Genet. 2015 Jun 15;24(12):3481-96. doi: 10.1093/hmg/ddv099. Epub 2015 Mar 17.

Neuronal identity genes regulated by super-enhancers are preferentially down-regulated in the striatum of Huntington's disease mice.

Author information

1
Neurogenetics and Translational Medicine Department.
2
Microarray and Sequencing Platform and.
3
CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Institute of Biology Paris-Seine, 9 quai Saint Bernard, Paris 75005, France, Sorbonnes Universités, UPMC Université Paris 06, F-75005 Paris, France and.
4
Laboratory of Cognitive and Adaptive Neuroscience, CNRS/University of Strasbourg, UMR 7364, 12 rue Goethe, 67000 Strasbourg, France.
5
Functional Genomics and Cancer Department, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/University of Strasbourg, UMR 7104, 1 rue Laurent Fries, Illkirch 67404, France.
6
Neurogenetics and Translational Medicine Department, Laboratory of Cognitive and Adaptive Neuroscience, CNRS/University of Strasbourg, UMR 7364, 12 rue Goethe, 67000 Strasbourg, France karine.merienne@unistra.fr.

Abstract

Huntington's disease (HD) is a neurodegenerative disease associated with extensive down-regulation of genes controlling neuronal function, particularly in the striatum. Whether altered epigenetic regulation underlies transcriptional defects in HD is unclear. Integrating RNA-sequencing (RNA-seq) and chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq), we show that down-regulated genes in HD mouse striatum associate with selective decrease in H3K27ac, a mark of active enhancers, and RNA Polymerase II (RNAPII). In addition, we reveal that decreased genes in HD mouse striatum display a specific epigenetic signature, characterized by high levels and broad patterns of H3K27ac and RNAPII. Our results indicate that this signature is that of super-enhancers, a category of broad enhancers regulating genes defining tissue identity and function. Specifically, we reveal that striatal super-enhancers display extensive H3K27 acetylation within gene bodies, drive transcription characterized by low levels of paused RNAPII, regulate neuronal function genes and are enriched in binding motifs for Gata transcription factors, such as Gata2 regulating striatal identity genes. Together, our results provide evidence for preferential down-regulation of genes controlled by super-enhancers in HD striatum and indicate that enhancer topography is a major parameter determining the propensity of a gene to be deregulated in a neurodegenerative disease.

PMID:
25784504
DOI:
10.1093/hmg/ddv099
[Indexed for MEDLINE]

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