title: THAP1, the gene mutated in DYT6 dystonia, autoregulates its own expression.
abstract: 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 480bp-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.
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Alev
authors.initials: A
authors.lastname: Erogullari
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Hollstein
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Seibler
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Braunholz
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Koschmidder
authors.affiliation: Institute of Physiology, Center of Structural and Cell Biology in Medicine, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Depping
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, University of Luebeck, Luebeck 23538, Germany; Institut für Humangenetik, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Eckhold
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Thora
authors.initials: T
authors.lastname: Lohnau
authors.affiliation: Institut für Humangenetik, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Grünewald
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rakovic
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck 23538, Germany. Electronic address: katja.lohmann@neuro.uni-luebeck.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, University of Luebeck, Luebeck 23538, Germany.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004421:Dystonia / Q000235:genetics*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C474080:THAP1 protein, human
keywords: Compensation; Dystonia; Expression; Feed-back loop; Regulation; Transcription