Transcription elongation and tissue-specific somatic CAG instability
Agathi-Vasiliki Goula1, Agnieszka Stys, Jackson P K Chan
1Programme of Translational Medicine and Neurogenetics, Institute of Genetics and Molecular and Cellular Biology, UMR 7104-CNRS/INSERM/UdS, Illkirch, France.
Plos Genetics
|December 5, 2012
Summary
Somatic CAG/CTG repeat instability in Huntington's disease (HD) is linked to transcription. Tissue-specific transcription elongation, not initiation, correlates with CAG instability, suggesting a key role for elongation in disease progression.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- CAG/CTG repeat expansions cause diseases like Huntington's disease (HD).
- Repeat instability in somatic tissues accelerates disease progression.
- Mechanisms of repeat instability, including chromatin and transcription roles, are not fully understood.
Purpose of the Study:
- Investigate the relationship between CAG instability, chromatin structure, and transcription in HD.
- Determine the role of transcription in somatic CAG/CTG instability in vivo.
Main Methods:
- Utilized R6/1 and R6/2 HD transgenic mouse models.
- Analyzed CAG instability, transgene expression, chromatin accessibility, and histone modifications (H3K4me3, H3K9me2, H3K36me3).
- Assessed RNA Polymerase II (Pol II) initiation and elongation at the HD locus.
Main Results:
- CAG instability was higher in R6/2 mice compared to R6/1 mice.
- Increased transgene expression and chromatin accessibility correlated with higher CAG instability.
- Tissue-specific levels of elongating RNA Pol II and H3K36me3 correlated with CAG instability levels.
- Transcription elongation, not initiation, was linked to tissue-specific instability.
Conclusions:
- Transcription modulates somatic CAG instability in vivo.
- Transcription elongation, regulated in a tissue-dependent manner, contributes to tissue-selective CAG instability in HD.
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