Dysregulation of REST ‐regulated coding and non‐coding RNA s in a cellular model of Huntington's disease

Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in Huntington's disease ( HD ) brought about by altered interactions with the mutant Htt (muHtt) protein. Repressor Element‐1 Silencing Transcription Factor ( REST ) is a repressor whose association with Htt in the cytoplasm is disrupted in HD , leading to increased nuclear REST and concomitant repression of several neuronal‐specific genes, including brain‐derived neurotrophic factor ( Bdnf ). Here, we explored a wide set of HD dysregulated genes to identify direct REST targets whose expression is altered in a cellular model of HD but that can be rescued by knock‐down of REST activity. We found many direct REST target genes encoding proteins important for nervous system development, including a cohort involved in synaptic transmission, at least two of which can be rescued at the protein level by REST knock‐down. We also identified several micro RNA s (mi RNA s) whose aberrant repression is directly mediated by REST , including miR‐137, which has not previously been shown to be a direct REST target in mouse. These data provide evidence of the contribution of inappropriate REST ‐mediated transcriptional repression to the widespread changes in coding and non‐coding gene expression in a cellular model of HD that may affect normal neuronal function and survival.