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Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.
- Source :
-
Nature neuroscience [Nat Neurosci] 2016 Apr; Vol. 19 (4), pp. 623-33. Date of Electronic Publication: 2016 Feb 22. - Publication Year :
- 2016
-
Abstract
- To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo.
- Subjects :
- Animals
Cerebral Cortex pathology
Cerebral Cortex physiology
Corpus Striatum pathology
Corpus Striatum physiology
Female
Gene Knock-In Techniques methods
Huntingtin Protein
Male
Mice
Mice, Inbred C57BL
Gene Regulatory Networks genetics
Genomics methods
Nerve Tissue Proteins genetics
Nuclear Proteins genetics
Proteomics methods
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1726
- Volume :
- 19
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Nature neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 26900923
- Full Text :
- https://doi.org/10.1038/nn.4256