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

Lulin Huang; Li Fang; Qian Liu; Abolfazl Doostparast Torshizi; Kai Wang

doi:10.1016/j.gendis.2021.05.004

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

更新时间：2022-06-24

- Integrated analysis on transcriptome and behaviors defines HTT repeat-dependent network modules in Huntington's disease
- Genes & Diseases Vol. 9, Issue 2, (2022)
- 作者机构：
  
  1. The 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,Sichuan,Chengdu,PR China,610054
  2. Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia,PA,USA,19104
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2021.05.004
  CLC：
- Published：2022，
  
  Published Online：1 March 2022，
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Lulin Huang, Li Fang, Qian Liu, et al. Integrated analysis on transcriptome and behaviors defines HTT repeat-dependent network modules in Huntington's disease. [J]. Genes & Diseases 9(2).(2022)
DOI：

Lulin Huang, Li Fang, Qian Liu, et al. Integrated analysis on transcriptome and behaviors defines HTT repeat-dependent network modules in Huntington's disease. [J]. Genes & Diseases 9(2).(2022) DOI： 10.1016/j.gendis.2021.05.004.

摘要

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.

关键词

Keywords

BehaviorsCAG repeatHuntington's diseaseMiceSingle-cell RNA sequencingSmall chemicalsStriatumTranscriptome

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