Nucleolar dysfunction in Huntington's disease

• CBP is localized into the nucleus and acetylates UBF.
• The decreased level of UBF acetylation is correlated with the reduction of rDNA transcription in HD.
• Trimethyation of UBF leads to nucleolar chromatin condensation and impairs rDNA transcription in HD.
• Epigenetic modifications of UBF contribute to the nucleolus-dependent pathogenesis of HD.

Huntington's disease (HD) is a fatal genetic disorder characterized by triad clinical symptoms of chorea, emotional distress, and cognitive decline. Genetic mutation in HD is identified by an expansion of CAG repeats coding for glutamine (Q) in exon 1 of the huntingtin (htt) gene. The exact mechanism on how mutant htt leads to the selective loss of medium spiny neurons (MSNs) in the striatum is still unknown. Recent studies suggest that nucleolar stress and dysfunction are linked to the pathogenesis of HD. Alterations of the nucleolar activity and integrity contribute to deregulation of ribosomal DNA (rDNA) transcription in HD pathogenesis. Furthermore, epigenetic modifications in the nucleolus are associated with neuronal damage in HD. In this review, we discuss about how post-translational modifications of upstream binding factor (UBF) are affected by histone acetyltransferase and histone methyltransferase and involved in the transcriptional regulation of rDNA in HD. The understanding of epigenetic modulation of UBF-dependent rDNA transcription in the nucleolus may lead to the identification of novel pathological markers and new therapeutic targets to treat HD. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.