Partners in crime: bidirectional transcription in unstable microsatellite disease

Abstract

Nearly two decades have passed since the discovery that the expansion of microsatellite trinucleotide repeats is responsible for a prominent class of neurological disorders, including Huntington disease and fragile X syndrome. These hereditary diseases are characterized by genetic anticipation or the intergenerational increase in disease severity accompanied by a decrease in age-of-onset. The revelation that the variable expansion of simple sequence repeats accounted for anticipation spawned a number of pathogenesis models and a flurry of studies designed to reveal the molecular events affected by these expansions. This work led to our current understanding that expansions in protein-coding regions result in extended homopolymeric amino acid tracts, often polyglutamine or polyQ, and deleterious protein gain-of-function effects. In contrast, expansions in noncoding regions cause RNA-mediated toxicity. However, the realization that the transcriptome is considerably more complex than previously imagined, as well as the emerging regulatory importance of antisense RNAs, has blurred this distinction. In this review, we summarize evidence for bidirectional transcription of microsatellite disease genes and discuss recent suggestions that some repeat expansions produce variable levels of both toxic RNAs and proteins that influence cell viability, disease penetrance and pathological severity.

Figure 1.

Potential roles for bidirectional transcription in SCA8 pathogenesis. Transcription of the sense (ATXN8) strand (blue ribbon) results in the synthesis of the ataxin8 polyQ (PolyQ) protein from the CAG^exp transcript (blue line). While a direct role for ataxin8 has not been demonstrated, polyQ (green) expression in other microsatellite expansion disorders, such as Huntington disease, disrupts multiple regulatory pathways (transcription, ubiquitin proteasomal system, autophagy, synaptic transmission). In contrast, ATXN8OS transcription produces a toxic CUG^exp RNA (red line, RNA stem-loop with U–U mismatches shown as bulged triangles) that reverts RNA splicing patterns to a fetal pattern due to MBNL1 sequestration and CELF1 hyperphosphorylation. Also shown is transcriptional interference induced by divergently transcribing RNA polymerase II complexes (Pol II).