THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation

Aguiló, Francesca; Zakirova, Zuchra; Nolan, Kevin B.; Wagner, Ryan T.; Sharma, Rajal; Hogan, Megan S.; Wei, Chengguo; Sun, Yifei; Walsh, Martin J.; Kelley, Kevin; Zhang, Weijia; Ozelius, Laurie J.; Gonzalez‐Alegre, Pedro; Zwaka, Thomas P.; Ehrlich, Michelle E.

doi:10.1016/j.stemcr.2017.04.032

Cited by 30 publications

(40 citation statements)

References 41 publications

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“…To determine if any of the DEGs from the RNA-Seq datasets were bound directly by THAP1, we compared them against two publicly available THAP1 ChIP-Seq datasets, one from human ENCODE K562 cells, and the other from mouse ES cells [ 14 ]. The Thap1 +/- cerebellum had the greatest number of overlapping genes when compared to both ChIP-Seq datasets, with a total of 32 overlapping genes when compared to the mouse ES cell data and 39 overlapping genes when compared to the K562 dataset ( S11 Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Little is known about the biological function of THAP1, particularly in neurons, although there is a neuron-specific DNA-binding THAP1-like-immunoreactive species [ 10 ]. There is also an alternatively spliced form lacking Exon2 which functionally does not substitute for the full-length protein [ 14 ] and is normally present at very low levels in the brain [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Genetically engineered mice with heterozygote Thap1 mutations, either C54Y or ΔExon2, display structural abnormalities of the deep cerebellar nuclei and deficits on motor tasks without overt dystonia [ 18 ]. Both mutations are early embryonic lethal when homozygote [ 18 ], and in mouse embryonic stem cells, lead to decreased viability and neuroectodermal differentiation [ 14 ]. The cell cycle is the major dysregulated pathway that emerged from microarray assays of HUVECs with up- or down-regulation of THAP1 and of human lymphoblasts harboring a disease-associated intronic variant of THAP1 [ 19 , 20 ], but was not enriched in ES cells [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…As a transcription factor, THAP1 can regulate expression of genes, while mutant THAP1 could lose these function and (Cayrol et al 2007). Mouse THAP1 is essential for regulating genes related to embryonic stem cells (mESC) potential, survival, and proliferation (Aguilo et al 2017). In mouse brain, THAP1 mutations or deletions lead to dysregulation of genes involved in pathways of eIF2α signaling, mitochondrial dysfunction, and neuron projection development (Zakirova et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia

et al. 2020

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Mutations in THAP1 (THAP domain-containing apoptosis-associated protein 1) are responsible for DYT6 dystonia. Until now, more than eighty different mutations in THAP1 gene have been found in patients with primary dystonia, and two third of them are missense mutations. The potential pathogeneses of these missense mutations in human are largely elusive. In the present study, we generated stable transfected human neuronal cell lines expressing wild-type or mutated THAP1 proteins found in DYT6 patients. Transcriptional profiling using microarrays revealed a set of 28 common genes dysregulated in two mutated THAP1 (S21T and F81L) overexpression cell lines suggesting a common mechanism of these mutations. ChIP-seq showed that THAP1 can bind to the promoter of one of these genes, superoxide dismutase 2 (SOD2). Overexpression of THAP1 in SK-N-AS cells resulted in increased SOD2 protein expression, whereas fibroblasts from THAP1 patients have less SOD2 expression, which indicates that SOD2 is a direct target gene of THAP1. In addition, we show that some THAP1 mutations (C54Y and F81L) decrease the protein stability which might also be responsible for altered transcription regulation due to dosage insufficiency. Taking together, the current study showed different potential pathogenic mechanisms of THAP1 mutations which lead to the same consequence of DYT6 dystonia.

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“…Consistent with that, rs73534533 CA + AA genotypes are associated with a significant increase in mRNA expression levels of MSRA in lymphobplastoid cell lines, leading to suppressive genic effects on NSCLC. Moreover, rs73534533 might have effects on tumor progression through disruption of seven transcription regulators motifs, including homeobox protein Hox-B13, which might influence angiogenesis and epithelial cell maturation 51 ; paired box protein Pax-4, which is correlated with cell differentiation and apoptotic process 52 ; and THAP Domain Containing 1, which regulates endothelial cell proliferation and G1/S cell-cycle progression 53 . Taken together, this evidence may partly explain the biological and molecular mechanisms underlying the observed associations.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in RUNX3, AMD1 and MSRA in the methionine metabolic pathway and survival in nonsmall cell lung cancer patients

Chen

Liu

et al. 2019

Intl Journal of Cancer

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Abnormal methionine dependence in cancer cells has led to methionine restriction as a potential therapeutic strategy. We hypothesized that genetic variants involved in methionine-metabolic genes are associated with survival in non-small cell lung cancer (NSCLC) patients. Therefore, we investigated associations of 16,378 common single-nucleotide polymorphisms (SNPs) in 97 methionine-metabolic pathway genes with overall survival (OS) in NSCLC patients using genotyping data from two published genome-wide association study (GWAS) datasets. In the single-locus analysis, 1,005 SNPs were significantly associated with NSCLC OS (P < 0.05 and false-positive report probability < 0.2) in the discovery dataset. Three SNPs (RUNX3 rs7553295G>T, AMD1 rs1279590G>A and MSRA rs73534533C>A) were replicated in the validation dataset and their meta-analysis showed that adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and Pmeta=2.86 x 10−6, 0.81 (0.73-0.91) and Pmeta=4.63 x 10−4, and 0.77 (0.68-0.89) and Pmeta=2.07 x 10−4, respectively). A genetics score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (Ptrend <.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between these genotypes and gene mRNA expression levels. Moreover, differential expression analysis further supported a tumor-suppressive effect of MSRA, with lower mRNA levels in both lung squamous carcinoma and adenocarcinoma (P <.0001 and <.0001, respectively) than in adjacent normal tissues. Additionally, low mutation rates of these three genes indicated the critical roles of these functional SNPs in cancer progression. Taken together, these genetic variants of methionine-metabolic pathway genes may be promising predictors of survival in NSCLC patients.

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THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation

Cited by 30 publications

References 41 publications

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

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

Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia

Genetic variants in RUNX3, AMD1 and MSRA in the methionine metabolic pathway and survival in nonsmall cell lung cancer patients

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