TY - JOUR
T1 - DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family
AU - Cheng, Fubo
AU - Zheng, Wenxu
AU - Barbuti, Peter Antony
AU - Bonsi, Paola
AU - Liu, Chang
AU - Casadei, Nicolas
AU - Ponterio, Giulia
AU - Meringolo, Maria
AU - Admard, Jakob
AU - Dording, Claire Marie
AU - Yu-Taeger, Libo
AU - Nguyen, Huu Phuc
AU - Grundmann-Hauser, Kathrin
AU - Ott, Thomas
AU - Houlden, Henry
AU - Pisani, Antonio
AU - Krüger, Rejko
AU - Riess, Olaf
N1 - The research was partially supported by the Fortüne junior grant, University of Tuebingen (FC: 2407-0-0) and the Deutsche Forschungsgemeinschaft (DFG) (OR: RI 682/19-1 AOBJ663994). NGS sequencing methods were performed with the support of the DFG-funded NGS Competence Center Tübingen (INST 37/1049-1). Work of PB and RK is supported by an Excellence Award for Research (PEARL) from the Fonds National de Recherche Luxembourg (to RK; FNR/P13/6682797).
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PY - 2022/11/21
Y1 - 2022/11/21
N2 - DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients' frontal cortex, THAP1 patients' induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.
AB - DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients' frontal cortex, THAP1 patients' induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.
KW - epigenetics
KW - primary dystonia
KW - SP1 family
KW - THAP1 dystonia
KW - therapeutic targets
UR - http://www.scopus.com/inward/record.url?scp=85135883473&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35015830
U2 - 10.1093/brain/awac001
DO - 10.1093/brain/awac001
M3 - Article
C2 - 35015830
SN - 0006-8950
VL - 145
SP - 3968
EP - 3984
JO - Brain
JF - Brain
IS - 11
ER -