THAP1, the gene mutated in DYT6 dystonia, autoregulates its own expression

Erogullari, Alev; Hollstein, Ronja; Seibler, Philip; Braunholz, Diana; Koschmidder, Eva; Depping, Reinhard; Eckhold, Juliane; Lohnau, Thora; Gillessen‐Kaesbach, Gabriele; Grünewald, Anne; Raković, Aleksandar; Lohmann, Katja; Kaiser, Frank J.

doi:10.1016/j.bbagrm.2014.07.019

Cited by 20 publications

(20 citation statements)

References 23 publications

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“…Secondary motifs overrepresented in THABS overlapped with the binding sequence for RE-silencing transcription factor (REST), which represses the expression of neuronal genes in differentiated non-neuronal cells (Ballas et al., 2005), and Yin Yang 1 (YY1), which plays multiple roles in the development of the central and peripheral nervous systems (He and Casaccia-Bonnefil, 2008; Figure 4G, right panel). Consistent with previous reports, inspection of individual gene tracks showed THAP1 binding at the core promoter of Thap1 and Tor1A (Erogullari et al., 2014, Gavarini et al., 2010, Kaiser et al., 2010), thus validating our approach (Figures 5A and 5B, left panel). ChIP-qPCR using anti-THAP1 antibody confirmed THAP1 occupancy at these sites in WT but not in Thap1 C54Y and Thap1 ΔExon2 ESCs (Figures 5A and 5B, right panel), and at promoters of the cell-cycle genes Aurora A kinase ( Aurka ) and tumor protein p53 ( Trp53 ), at the apoptosis genes Bcl-2-associated death promoter ( Bad ) and DNA fragmentation factor subunit beta ( Dffb ), and at the splicing factor 3a subunit 2 ( Sf3a2 ).…”

Section: Resultssupporting

confidence: 92%

“…Genotypes of wild-type (WT), Thap1 C54Y / C54Y , and Thap1 ΔExon2 / ΔExon2 ESCs were analyzed by PCR and compared with WT, Thap1 C54Y / + , and Thap1 ΔExon2 / + heterozygote mice (Figure 1B). Consistent with THAP1 autorepression (Erogullari et al., 2014) and failure of THAP1 C54Y to bind at the Tor1a promoter (Gavarini et al., 2010), Thap1 C54Y cells exhibited higher levels of Thap1 mRNA than WT ESCs, whereas full-length Thap1 mRNA was undetectable in Thap1 ΔExon2 ESCs (Figure 1C). THAP1 antibodies recognize several THAP1-like immunoreactive (THAP1-LIR) species (Ortiz-Virumbrales et al., 2014).…”

Section: Resultssupporting

confidence: 63%

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THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation

et al. 2017

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SummaryTHAP1 (THAP [Thanatos-associated protein] domain-containing, apoptosis-associated protein 1) is a ubiquitously expressed member of a family of transcription factors with highly conserved DNA-binding and protein-interacting regions. Mutations in THAP1 cause dystonia, DYT6, a neurologic movement disorder. THAP1 downstream targets and the mechanism via which it causes dystonia are largely unknown. Here, we show that wild-type THAP1 regulates embryonic stem cell (ESC) potential, survival, and proliferation. Our findings identify THAP1 as an essential factor underlying mouse ESC survival and to some extent, differentiation, particularly neuroectodermal. Loss of THAP1 or replacement with a disease-causing mutation results in an enhanced rate of cell death, prolongs Nanog, Prdm14, and/or Rex1 expression upon differentiation, and results in failure to upregulate ectodermal genes. ChIP-Seq reveals that these activities are likely due in part to indirect regulation of gene expression.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 63%

THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation

et al. 2017

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“…Third, only a small number of DEGs were altered in both genotypes ( S5 Table ). For both mutations, the log2 values are low for what would be predicted for a transcription factor [ 53 ], perhaps in the presence of the C54Y mutation due to compensatory auto-up-regulation of Thap1 [ 18 , 54 ]. Reports of dystonia patients with homozygous THAP1 mutations with non-manifesting heterozygous parents [ 55 , 56 ] highlight dosage dependent effects of THAP1 mutations.…”

Section: Discussionmentioning

confidence: 99%

Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions

et al. 2018

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Dystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse and it is unknown whether their pathogenesis converges on shared pathways. Mutations in THAP1 [THAP (Thanatos-associated protein) domain containing, apoptosis associated protein 1], a ubiquitously expressed transcription factor with DNA binding and protein-interaction domains, cause dystonia, DYT6. There is a unique, neuronal 50-kDa Thap1-like immunoreactive species, and Thap1 levels are auto-regulated on the mRNA level. However, THAP1 downstream targets in neurons, and the mechanism via which it causes dystonia are largely unknown. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1 C54Y or ΔExon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic LongTerm Depression, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays were consistent with those enrichments, and the plasticity defects were partially corrected by salubrinal. Notably, several of these pathways were recently implicated in other forms of inherited dystonia, including DYT1. We conclude that dysfunction of these pathways may represent a point of convergence in the pathophysiology of several forms of inherited dystonia.

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“…Mutations in the THAP1 domain are thought to interrupt DNA binding, causing transcriptional dysregulation of THAP1 target genes [1]. A functional study in a THAP1 case with a frameshift mutation in the nuclear localizing signal region of THAP1 demonstrated an impaired nuclear import of mutant THAP1 in vitro [18]; THAP1 is reported to interact with the promoters of TOR1A , mutations of which cause DYT1 dystonia [19], TAF1 , implicated in DYT3 dystonia [20], and recently THAP1 has been reported to autoregulate its own expression [21]. Hence, studies of biochemical and cellular mechanisms may provide a link to abnormal motor control in DYT6 dystonia.…”

Section: Discussionmentioning

confidence: 99%

DYT6 Dystonia: A Neuropathological Study

Paudel¹,

Li²,

Hardy³

et al. 2015

Neurodegener Dis

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Background: Mutations in the thanatos-associated protein domain containing apoptosis-associated protein 1 gene (THAP1) are responsible for adult-onset isolated dystonia (DYT6). However, no neuropathological studies of genetically proven DYT6 cases have been previously reported. Objective: We report the first detailed neuropathological investigation carried out on two DYT6 brains. Methods: Genetic screening for THAP1 gene mutations using standard Sanger polymerase chain reaction sequencing identified 2 cases, 1 with a known pathogenic mutation and the other with a novel mutation. A detailed neuropathological assessment of the cases was performed. Results: Both DYT6 cases showed no significant neurodegeneration and no specific disease-related pathology. Conclusions: No neuropathological features that could be defined as hallmark features of DYT6 dystonia were identified. Our study supports the notion that in isolated dystonia, there is no significant neurodegeneration or morphological lesions that can be identified using routine methods.

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THAP1, the gene mutated in DYT6 dystonia, autoregulates its own expression

Cited by 20 publications

References 23 publications

THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation

THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation

Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions

DYT6 Dystonia: A Neuropathological Study

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