The expansion of CAG/CTG repeats is responsible for many diseases, including 
Huntington's disease (HD) and myotonic dystrophy 1. CAG/CTG expansions are 
unstable in selective somatic tissues, which accelerates disease progression. 
The mechanisms underlying repeat instability are complex, and it remains unclear 
whether chromatin structure and/or transcription contribute to somatic CAG/CTG 
instability in vivo. To address these issues, we investigated the relationship 
between CAG instability, chromatin structure, and transcription at the HD locus 
using the R6/1 and R6/2 HD transgenic mouse lines. These mice express a similar 
transgene, albeit integrated at a different site, and recapitulate HD 
tissue-specific instability. We show that instability rates are increased in 
R6/2 tissues as compared to R6/1 matched-samples. High transgene expression 
levels and chromatin accessibility correlated with the increased CAG instability 
of R6/2 mice. Transgene mRNA and H3K4 trimethylation at the HD locus were 
increased, whereas H3K9 dimethylation was reduced in R6/2 tissues relative to 
R6/1 matched-tissues. However, the levels of transgene expression and these 
specific histone marks were similar in the striatum and cerebellum, two tissues 
showing very different CAG instability levels, irrespective of mouse line. 
Interestingly, the levels of elongating RNA Pol II at the HD locus, but not the 
initiating form of RNA Pol II, were tissue-specific and correlated with CAG 
instability levels. Similarly, H3K36 trimethylation, a mark associated with 
transcription elongation, was specifically increased at the HD locus in the 
striatum and not in the cerebellum. Together, our data support the view that 
transcription modulates somatic CAG instability in vivo. More specifically, our 
results suggest for the first time that transcription elongation is regulated in 
a tissue-dependent manner, contributing to tissue-selective CAG instability.