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Huntington's disease (HD) is caused by a genetically mutated huntingtin (mHtt) protein with expanded polyQ stretch, which impairs cytosolic sequestration of the repressor element‐1 silencing transcription factor (REST), resulting in excessive nuclear REST and subsequent repression of neuronal genes. We recently demonstrated that REST undergoes extensive, context‐dependent alternative splicing, of which exon‐3 skipping (∆E3)—a common event in human and nonhuman primates—causes loss of a motif critical for REST nuclear targeting. This study aimed to determine whether ∆E3 can be targeted to reduce nuclear REST and rescue neuronal gene expression in mouse striatal‐derived, mHtt‐expressing STHdhQ111/Q111 cells—a well‐established cellular model of HD. We designed two morpholino antisense oligos (ASOs) targeting the splice sites of Rest E3 and examined their effects on ∆E3, nuclear Rest accumulation and Rest‐controlled gene expression in STHdhQ111/Q111 cells. We found that (1) the ASOs treatment significantly induced ∆E3, reduced nuclear Rest, and rescued transcription and/or mis‐splicing of specific neuronal genes (e.g. Syn1 and Stmn2) in STHdhQ111/Q111 cells; and (2) the ASOs‐induced transcriptional regulation was dependent on ∆E3 induction and mimicked by siRNA‐mediated knock‐down of Rest expression. Our findings demonstrate modulation of nuclear REST by ∆E3 and its potential as a new therapeutic target for HD and provide new insights into environmental regulation of genome function and pathogenesis of HD. As ∆E3 is modulated by cellular signalling and linked to various types of cancer, we anticipate that ∆E3 contributes to environmentally tuned REST function and may have a broad range of clinical implications.

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