We propose a Systems Biology approach to map transcriptional regulatory networks and related signaling pathways that are altered in Huntington's disease (HD), a fatal autosomal dominant neurodegenerative disorder. HD is caused by a CAG expansion leading to a polyglutamine extension in the huntingtin protein and is characterized by problems with movement, cognition and behavioral function. Although the genetic basis for the disease is clear, the mechanism by which huntingtin causes the observed symptoms remains enigmatic. Our approach is based on the hypothesis that many of the genes previously linked to HD through proteomic and genetic screens are connected through signaling pathways to many of the transcriptional changes that have been reported in HD studies. Identifying these pathways would provide critical new insights into the molecular changes that underlie the disease, and could lead to novel therapeutic strategies. We have recently developed a technique for identifying such signaling pathways through a combination of computational and experimental methods.
In Specific Aim 1 we will map out changes in recruitment of transcriptional regulatory proteins because these proteins lie at the interface between the signaling and expression changes.
In Specific Aim 2 we will computationally identify signaling changes """"""""upstream"""""""" of these regulators that link the transcriptional changes to the genetic and proteomic data. If successful, this approach will advance knowledge of the etiology of HD and provide a powerful new method for studying many human diseases.

Public Health Relevance

We propose a systems biology approach to understanding the molecular changes that occur in Huntington's disease. This project uses high-throughput experiments and computational modeling to reveal pathways that are altered in the disease and that may lead to new therapeutic approaches.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genomics, Computational Biology and Technology Study Section (GCAT)
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Krasnewich, Donna M
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Massachusetts Institute of Technology
Engineering (All Types)
Schools of Engineering
United States
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Pirhaji, Leila; Milani, Pamela; Leidl, Mathias et al. (2016) Revealing disease-associated pathways by network integration of untargeted metabolomics. Nat Methods 13:770-6
Gosline, Sara J C; Gurtan, Allan M; JnBaptiste, Courtney K et al. (2016) Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-transcriptional, and Histone Modification Measurements. Cell Rep 14:310-9
Tuncbag, Nurcan; Gosline, Sara J C; Kedaigle, Amanda et al. (2016) Network-Based Interpretation of Diverse High-Throughput Datasets through the Omics Integrator Software Package. PLoS Comput Biol 12:e1004879
Gosline, Sara J C; Oh, Coyin; Fraenkel, Ernest (2015) SAMNetWeb: identifying condition-specific networks linking signaling and transcription. Bioinformatics 31:1124-6
Lodato, Michael A; Ng, Christopher W; Wamstad, Joseph A et al. (2013) SOX2 co-occupies distal enhancer elements with distinct POU factors in ESCs and NPCs to specify cell state. PLoS Genet 9:e1003288
Huang, Shao-shan Carol; Clarke, David C; Gosline, Sara J C et al. (2013) Linking proteomic and transcriptional data through the interactome and epigenome reveals a map of oncogene-induced signaling. PLoS Comput Biol 9:e1002887
Lo, Kinyui Alice; Labadorf, Adam; Kennedy, Norman J et al. (2013) Analysis of in vitro insulin-resistance models and their physiological relevance to in vivo diet-induced adipose insulin resistance. Cell Rep 5:259-70
Vashishtha, Malini; Ng, Christopher W; Yildirim, Ferah et al. (2013) Targeting H3K4 trimethylation in Huntington disease. Proc Natl Acad Sci U S A 110:E3027-36
Ng, Christopher W; Yildirim, Ferah; Yap, Yoon Sing et al. (2013) Extensive changes in DNA methylation are associated with expression of mutant huntingtin. Proc Natl Acad Sci U S A 110:2354-9
Tuncbag, Nurcan; Braunstein, Alfredo; Pagnani, Andrea et al. (2013) Simultaneous reconstruction of multiple signaling pathways via the prize-collecting steiner forest problem. J Comput Biol 20:124-36

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