Integrated analysis on transcriptome and behaviors defines HTT repeat-dependent network modules in Huntington's disease

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.