Transcriptional regulatory networks underlying gene expression changes in Huntington's disease
Abstract Transcriptional changes occur presymptomatically and throughout Huntington's disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD. We reconstructed a genome‐scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by in...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-03-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20167435 |
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| _version_ | 1849331532113641472 |
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| author | Seth A Ament Jocelynn R Pearl Jeffrey P Cantle Robert M Bragg Peter J Skene Sydney R Coffey Dani E Bergey Vanessa C Wheeler Marcy E MacDonald Nitin S Baliga Jim Rosinski Leroy E Hood Jeffrey B Carroll Nathan D Price |
| author_facet | Seth A Ament Jocelynn R Pearl Jeffrey P Cantle Robert M Bragg Peter J Skene Sydney R Coffey Dani E Bergey Vanessa C Wheeler Marcy E MacDonald Nitin S Baliga Jim Rosinski Leroy E Hood Jeffrey B Carroll Nathan D Price |
| author_sort | Seth A Ament |
| collection | DOAJ |
| description | Abstract Transcriptional changes occur presymptomatically and throughout Huntington's disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD. We reconstructed a genome‐scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by integrating a model of genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF‐target gene modules associated with age‐ and CAG repeat length‐dependent gene expression changes in Htt CAG knock‐in mouse striatum and replicated many of these associations in independent transcriptomic and proteomic datasets. Thirteen of 48 of these predicted TF‐target gene modules were also differentially expressed in striatal tissue from human disease. We experimentally validated a specific model prediction that SMAD3 regulates HD‐related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP‐seq) of mouse striatum. We found CAG repeat length‐dependent changes in the genomic occupancy of SMAD3 and confirmed our model's prediction that many SMAD3 target genes are downregulated early in HD. |
| format | Article |
| id | doaj-art-37a0a3de07ca4d86ab89638ff4d313a8 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2018-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-37a0a3de07ca4d86ab89638ff4d313a82025-08-20T03:46:32ZengSpringer NatureMolecular Systems Biology1744-42922018-03-0114311610.15252/msb.20167435Transcriptional regulatory networks underlying gene expression changes in Huntington's diseaseSeth A Ament0Jocelynn R Pearl1Jeffrey P Cantle2Robert M Bragg3Peter J Skene4Sydney R Coffey5Dani E Bergey6Vanessa C Wheeler7Marcy E MacDonald8Nitin S Baliga9Jim Rosinski10Leroy E Hood11Jeffrey B Carroll12Nathan D Price13Institute for Systems BiologyInstitute for Systems BiologyBehavioral Neuroscience Program, Department of Psychology, Western Washington UniversityBehavioral Neuroscience Program, Department of Psychology, Western Washington UniversityBasic Sciences Division, Fred Hutchinson Cancer Research CenterBehavioral Neuroscience Program, Department of Psychology, Western Washington UniversityInstitute for Systems BiologyMolecular Neurogenetics Unit, Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Harvard Medical SchoolMolecular Neurogenetics Unit, Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Harvard Medical SchoolInstitute for Systems BiologyCHDI Management, CHDI FoundationInstitute for Systems BiologyBehavioral Neuroscience Program, Department of Psychology, Western Washington UniversityInstitute for Systems BiologyAbstract Transcriptional changes occur presymptomatically and throughout Huntington's disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD. We reconstructed a genome‐scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by integrating a model of genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF‐target gene modules associated with age‐ and CAG repeat length‐dependent gene expression changes in Htt CAG knock‐in mouse striatum and replicated many of these associations in independent transcriptomic and proteomic datasets. Thirteen of 48 of these predicted TF‐target gene modules were also differentially expressed in striatal tissue from human disease. We experimentally validated a specific model prediction that SMAD3 regulates HD‐related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP‐seq) of mouse striatum. We found CAG repeat length‐dependent changes in the genomic occupancy of SMAD3 and confirmed our model's prediction that many SMAD3 target genes are downregulated early in HD.https://doi.org/10.15252/msb.20167435Huntington's diseaseSMAD3transcription factortranscriptional regulatory networks |
| spellingShingle | Seth A Ament Jocelynn R Pearl Jeffrey P Cantle Robert M Bragg Peter J Skene Sydney R Coffey Dani E Bergey Vanessa C Wheeler Marcy E MacDonald Nitin S Baliga Jim Rosinski Leroy E Hood Jeffrey B Carroll Nathan D Price Transcriptional regulatory networks underlying gene expression changes in Huntington's disease Molecular Systems Biology Huntington's disease SMAD3 transcription factor transcriptional regulatory networks |
| title | Transcriptional regulatory networks underlying gene expression changes in Huntington's disease |
| title_full | Transcriptional regulatory networks underlying gene expression changes in Huntington's disease |
| title_fullStr | Transcriptional regulatory networks underlying gene expression changes in Huntington's disease |
| title_full_unstemmed | Transcriptional regulatory networks underlying gene expression changes in Huntington's disease |
| title_short | Transcriptional regulatory networks underlying gene expression changes in Huntington's disease |
| title_sort | transcriptional regulatory networks underlying gene expression changes in huntington s disease |
| topic | Huntington's disease SMAD3 transcription factor transcriptional regulatory networks |
| url | https://doi.org/10.15252/msb.20167435 |
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