Genome-scale transcriptional regulatory network models for the mouse and human striatum predict roles for SMAD3 and other transcription factors in Huntington's disease
By
Seth Ament,
Jocelynn R Pearl,
Robert M. Bragg,
Peter J Skene,
Sydney R. Coffey,
Dani E Bergey,
Chris L Plaisier,
Vanessa C Wheeler,
Marcy E MacDonald,
Nitin S Baliga,
Jim Rosinski,
Leroy Hood,
Jeffrey B Carroll,
Nathan D. Price
Posted 10 Nov 2016
bioRxiv DOI: 10.1101/087114
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 TFs in the mouse striatum by integrating a model of the 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 Htt allele-dependent gene expression changes in the mouse striatum, and replicated many of these associations in independent transcriptomic and proteomic datasets. Strikingly, many of these predicted target genes were also differentially expressed in striatal tissue from human disease. We experimentally validated a key model prediction that SMAD3 regulates HD-related gene expression changes using chromatin immunoprecipitation and deep sequencing (ChIP-seq) of mouse striatum. We found Htt allele-dependent changes in the genomic occupancy of SMAD3 and confirmed our model's prediction that many SMAD3 target genes are down-regulated early in HD. Importantly, our study provides a mouse and human striatal-specific TRN and prioritizes a hierarchy of transcription factor drivers in HD.
Download data
- Downloaded 925 times
- Download rankings, all-time:
- Site-wide: 45,037
- In systems biology: 872
- Year to date:
- Site-wide: 134,534
- Since beginning of last month:
- Site-wide: 203,468
Altmetric data
Downloads over time
Distribution of downloads per paper, site-wide
PanLingua
News
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!