Gene expression-based profiling for studying dystonia pathogenisis
Hime, Audrey Elise
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This project mainly focuses on DYT6 dystonia and its causative gene: THAP1, which encodes a proposed transcription factor, THAP1, which exhibits sequencespecific and zinc-dependent DNA-binding activity. Over 50 pathogenic mutations have been identified in THAP1, and various clinical manifestations of DYT6 have been reported. The target genes of THAP1 are not fully understood, although some genes involved in cell cycle regulation have been shown to respond transcriptionally to changes in THAP1 levels. While a connection between THAP1 and cellular proliferation has been suggested, the exact relationship is still unclear, and there is an on-going interest in finding out more about the normal function(s) of THAP1 and how these functions are affected by DYT6 mutations. It can be difficult to interpret results from gene expression profiling to further understand a protein's biochemical activities and its basis for pathogenesis. Therefore this project uniquely inputs DYT6 gene expressionbased profiling data into the Connectivity Map, a signature profile reference database and software matching system, to identify known compounds that predict similar and opposite biological signatures as patients with DYT6. The results of this CMAP query show that compounds with strong positive scores, including HDAC inhibitors, HSP90 inhibitors, and phenothiazines, all are associated in the literature with antiproliferative effects. Compounds with strong negative scores show evidence of promoting cell cycle re-entry as well as neurogenesis, which may be considered to be part of a reverse signature of decreased proliferation. Hence bioinformatics analysis may provide clues to THAP1 and its biochemical mechanism of action, specifically in relation to proliferation and the cell cycle.
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