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B11 Identification Of An Epigenetic Signature In Huntington’s Disease Mouse Striatum
  1. K Merienne,
  2. MA Jreda,
  3. C Keime,
  4. S Le Gras,
  5. I Davidson
  1. IGBMC-CNRS/INSERM/University of Strasbourg (UMR7104), 1 Rue Laurent Fries, 67404 Illkirch, France

Abstract

Transcriptional dysregulation is a central mechanism of Huntington’s disease (HD) pathogenesis. Gene expression changes are extensive, particularly in the striatum, but specific, defining a transcriptomic signature enriched in neuronal genes. Epigenetic mechanisms control transcription, suggesting that epigenetic alterations might contribute to HD transcriptional dysregulation. To address this question, we combined RNA-sequencing (RNA-seq) and chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq) on the striatum of HD R6/1 transgenic and control mice. ChIP-seq experiments were performed using antibodies to RNAPII and H3K27ac, a histone modification marking active enhancers. Integrated analysis of RNA-seq and ChIP-seq data shows that H3K27ac and RNAPII are specifically decreased at down-regulated genes in R6/1 striatum relative to controls. Further data analysis reveals that genes targeted for down-regulation in R6/1 striatum exhibit a specific RNAPII and H3K27ac signature. This signature defines neuronal genes and identifies genes with elevated levels of RNAPII at gene body relative to transcription start site (e.g. RNAPII non-paused genes). H3K27ac occupancy parallels that of RNAPII and is elevated and spread throughout the body of the genes exhibiting the signature, suggesting that the signature delineates genes regulated through super-enhancers. Together, our results indicate that striatal RNAPII non-paused genes are under control of super-enhancers, regulate neuronal genes and are preferentially down-regulated in HD striatum. We anticipate that specific targeting of RNAPII non-paused genes might be a promising therapeutic avenue for HD.

KeyWords
  • Epigenetics
  • ChIP-seq
  • RNA-seq
  • striatum
  • HD mice

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