Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
Volume 1839, Issue 11, Pages 1196-1204Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagrm.2014.07.019
Keywords
Transcription; Regulation; Dystonia; Feed-back loop; Compensation; Expression
Categories
Funding
- German Research Foundation [LO 1555/3-2]
- University of Lubeck Schwerpunktprogramm: Medizinische Genetik - Von seltenen Varianten zur Krankheitsentstehung
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THAP1 encodes a transcription factor but its regulation is largely elusive. TOR1A was shown to be repressed by THAP1 in vitro. Notably, mutations in both of these genes lead to dystonia (DYT6 or DYT1). Surprisingly, expressional changes of TOR1A in THAP1 mutation carriers have not been detected indicating additional levels of regulation. Here, we investigated whether THAP1 is able to autoregulate its own expression. Using in-silico prediction, luciferase reporter gene assays, and (quantitative) chromatin immunoprecipitation (ChIP), we defined the THAP1 minimal promoter to a 480 bp-fragment and demonstrated specific binding of THAP1 to this region which resulted in repression of the THAP1 promoter. This autoregulation was disturbed by different DYT6-causing mutations. Two mutants (Ser6Phe, Arg13His) were shown to be less stable than wildtype THAP1 adding to the effect of reduced binding to the THAP1 promoter. Overexpressed THAP1 is preferably degraded through the proteasome. Notably, endogenous THAP1 expression was significantly reduced in cells overexpressing wildtype THAP1 as demonstrated by quantitative PCR. In contrast higher THAP1 levels were detected in induced pluripotent stem cell (iPS)-derived neurons from THAP1 mutation carriers. Thus, we identified a feedback-loop in the regulation of THAP1 expression and demonstrated that mutant THAP1 leads to higher THAP1 expression levels. This compensatory autoregulation may contribute to the mean age at onset in the late teen years or even reduced penetrance in some THAP1 mutation carriers. (C) 2014 Elsevier B.V. All rights reserved.
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