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Updated: Jul 13, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Integrated analysis on transcriptome and behaviors defines HTT repeat-dependent network modules in Huntington's
Lulin Huang1,2, Li Fang2, Qian Liu2
1The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Clinical Laboratory, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, PR China.
Insights
Huntington's disease (HD) research in knock-in mice links CAG repeat length to specific behaviors and gene expression changes. This study reveals correlations crucial for understanding HD and developing new treatments.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Huntington's disease (HD) is a genetic neurodegenerative disorder caused by CAG repeat expansion in the huntingtin (HTT) gene.
- Knock-in mouse models carrying expanded CAG repeats in the Htt gene recapitulate HD phenotypes, showing age- and genotype-dependent molecular network dysregulation.
- Previous research identified behavioral signatures for HD in these mice but lacked integrated analysis correlating specific behaviors with CAG repeat length.
Purpose of the Study:
- To conduct an integrated analysis correlating behavioral features with genotypes (CAG repeat expansions) in Htt CAG-knock-in mice.
- To investigate the landscape of behavioral features and gene expression correlations.
- To identify potential therapeutic targets for Huntington's disease.
Main Methods:
- Analysis of 445 mRNA and 445 microRNA samples from Htt CAG-knock-in mice.
- Comprehensive behavioral analysis using 396 PhenoCube and 111 NeuroCube behaviors.
- Integration of gene expression data with behavioral features and single-cell/spatial transcriptomics.
Main Results:
- Identification of 37 behavioral features significantly associated with CAG repeat length, including step count and hind limb stand duration.
- Association of these behavioral features with gene coexpression networks involved in neuronal dysfunction, supported by striatal single-cell and brain spatial gene expression data.
- Discovery of 15 chemicals, primarily dopamine and serotonin receptor modulators, showing significant responses related to genes enriched in behavioral features.
Conclusions:
- Abnormal neuronal signal transduction in the striatum is a key contributor to HD-related behaviors.
- The identified correlations provide a rich dataset for understanding HD pathogenesis.
- Findings offer valuable insights for future pharmacotherapeutic interventions for Huntington's disease.
Abstract:
Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes. Previous studies suggested dysregulated molecular networks in a CAG length genotype- and the age-dependent manner in brain tissues from knock-in mice carrying expanded Htt CAG repeats. Furthermore, a large-scale phenome analysis defined a behavioral signature for HD genotype in knock-in mice carrying expanded Htt CAG repeats. However, an integrated analysis correlating phenotype features with genotypes (CAG repeat expansions) was not conducted previously. In this study, we revealed the landscape of the behavioral features and gene expression correlations based on 445 mRNA samples and 445 microRNA samples, together with behavioral features (396 PhenoCube behaviors and 111 NeuroCube behaviors) in Htt CAG-knock-in mice. We identified 37 behavioral features that were significantly associated with CAG repeat length including the number of steps and hind limb stand duration. The behavioral features were associated with several gene coexpression groups involved in neuronal dysfunctions, which were also supported by the single-cell RNA sequencing data in the striatum and the spatial gene expression in the brain. We also identified 15 chemicals with significant responses for genes with enriched behavioral features, most of them are agonist or antagonist for dopamine receptors and serotonin receptors used for neurology/psychiatry. Our study provides further evidence that abnormal neuronal signal transduction in the striatum plays an important role in causing HD-related phenotypic behaviors and provided rich information for the further pharmacotherapeutic intervention possibility for HD.
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