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Significance Improved therapeutic intervention for neurodegenerative diseases, particularly early in progression of the disease course, is a critical need. Huntington’s disease (HD) is a paradigmatic disorder in this search in which vulnerable individuals can be identified early. This study focuses on the earliest stages of disease in a well-characterized animal model system. We identify early aberrant transcription and chromatin changes in affected brain regions of HD mice. The study identifies the Elk-1 transcription factor as a significant regulator of early transcriptional changes in HD. Enhanced Elk-1 levels exerted beneficial effects in an in vitro model and resulted in extensive restoration of transcriptional dysregulation in vivo. These results suggest a target for alleviating pathology in HD and other neuropsychiatric conditions.

Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington’s disease