A06 Huntington’s disease striatal super-enhancer signature

Abstract

Huntington’s disease (HD) is a progressive neurodegenerative disease, affecting primarily the striatum. Transcriptional dysregulation is believed to contribute to HD. However, the underlying mechanism is unclear. Using ChIPseq and RNAseq on the striatum of HD R6/1 transgenic mice, we found that down-regulated genes are enriched in striatal identity genes, controlled by a super-enhancer. H3K27ac, enhancer transcription and recruitment of RNA polymerase II (RNAPII) were selectively reduced at R6/1 striatal super-enhancers, indicating that altered super-enhancer activity underlies down-regulation of striatal identity genes in HD. Our 4Cseq data using R6/1 striatum further suggest that disruption of chromatin 3D architecture contributes to altered expression of striatal identity genes regulated by a super-enhancer. To investigate functional consequences of epigenetic alterations in HD, R6/1 mice were trained to learn striatum-dependent cognitive task. In contrast to wild-type (WT) animals, R6/1 mice were impaired in this task. ChIPseq data generated using the striatum of ‘trained’ and ‘home cage’ mice showed an increase of H3K27ac and RNAPII at genes implicated in synaptic plasticity and regulated by a super-enhancer, in trained vs home cage WT animals. However, this ‘plasticity’ signature was absent in trained R6/1 mice, suggesting that aberrant RNAPII dynamics and inadequate histone acetylation at these genes preclude synaptic plasticity and contribute to R6/1 behavioural deficits. Finally, we generated ChIPseq data using the striatum of HD patients and knockin mice. HD striatal ‘super-enhancer’ signature was conserved across models and our analyses further revealed that it establishes early, at presymptomatic stage.