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Transcriptional regulatory networks underlying gene expression changes in Huntington's disease
Seth A Ament1,2, Jocelynn R Pearl1,3,4, Jeffrey P Cantle5
1Institute for Systems Biology, Seattle, WA, USA.
Molecular Systems Biology
|March 28, 2018
Summary
Researchers mapped transcriptional regulatory networks in Huntington's disease (HD) by modeling transcription factor (TF) targets. They identified key gene modules and validated SMAD3's role in early HD gene expression changes.
Area of Science:
- Neuroscience
- Genetics
- Systems Biology
Background:
- Transcriptional dysregulation is a hallmark of Huntington's disease (HD), occurring early and persisting throughout the disease.
- Understanding transcriptional regulatory networks (TRNs) is crucial for elucidating HD pathogenesis.
Purpose of the Study:
- To reconstruct a genome-scale model of TRNs in the mouse striatum relevant to Huntington's disease.
- To identify specific transcription factor (TF)-target gene modules associated with HD progression and CAG repeat length.
Main Methods:
- Integrated genomic binding site data with transcriptome profiling from HD mouse models.
- Developed a genome-scale model of 718 transcription factors and their target genes in the mouse striatum.
- Utilized chromatin immunoprecipitation and deep sequencing (ChIP-seq) for experimental validation.
Main Results:
- Identified 48 differentially expressed TF-target gene modules linked to age and CAG repeat length in HD mouse striatum.
- Replicated findings in independent transcriptomic and proteomic datasets, with 13 modules showing differential expression in human HD.
- Experimentally validated SMAD3 as a regulator of HD-related gene expression, observing CAG repeat length-dependent changes in its genomic occupancy.
Conclusions:
- The study provides a comprehensive model of TRNs in HD, highlighting key regulatory modules.
- SMAD3 is identified as an early regulator in HD, with its target genes showing downregulation correlated with CAG repeat length.
- These findings offer insights into HD pathogenesis and potential therapeutic targets.
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