Polyglutamine (polyQ) disorders: the chromatin connection

Abstract

Polyglutamine (PolyQ)-related diseases are dominant late-onset genetic disorders that are manifested by progressive neurodegeneration, leading to behavioral and physical impairments. An increased body of evidence suggests that chromatin structure and epigenetic regulation are involved in disease pathology. PolyQ diseases often display an aberrant transcriptional regulation due to the disrupted function of histone-modifying complexes and altered interactions of the polyQ-extended proteins with chromatin-related factors. In this review we describe recent findings relating to the role of chromatin in polyQ diseases. We discuss the involvement of epigenetic-related factors and chromatin structure in genomic instability of CAG repeats; we describe changes in the expression and regulation of chromatin-related enzymes and in the levels and patterns of histone modifications in disease state; we illustrate the potential beneficial effects of different histone deacetylase (HDAC) inhibitors for the treatment of polyQ diseases, and we end by describing the potential use of human pluripotent stem cells and their differentiated derivatives for modeling polyQ diseases in vitro. Taken together, these accumulating studies strongly suggest that disrupted chromatin regulation may be directly involved with the pathophysiology of polyQ-related diseases.

Figure 1. Chromatin involvement in repeat instability. Some chromatin-related mechanisms that lead to repeat instability are depicted. Bidirectional transcription of long CAG repeats generates double stranded RNA, which is processed by the RNAi machinery into short RNAs that form hairpins. Those short CAG RNAs promote heterochromatin production, resulting in transcription inhibition (Refs. and 4). Double stranded RNA of CAG repeats can also induce apoptosis, leading to polyQ-related pathology (Refs. and 8). Perturbed CTCF binding and low Dnmt1 expression levels were also reported to promote instability (Refs. and 10).

Figure 2. Chromatin involvement in spinocerebellar ataxia type 7 (SCA7). CTCF binding at the promoter region of the ATXN7 gene promotes H3K27 methylation and antisense transcription from an alternative promoter. Impaired binding of CTCF abolishes H3K27 methylation and suppresses antisense transcription, along with induced polyQ-ATXN7 sense transcription, leading to disease phenotypes (Ref. 49). In addition, the ATXN7 protein (blue) is a component of both the SAGA and the SLIK HAT complexes. PolyQ-ATXN7 protein disrupts HAT activity of those complexes, resulting in chromatin disruption, retinal degeneration and SCA7 disease (Refs. ­46).