The role of Twist1 in mutant huntingtin-induced transcriptional alterations
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA475260 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7281230.fastq.gz | Fastqsanger.gz | |||
| SRR7281231.fastq.gz | Fastqsanger.gz | |||
| SRR7281232.fastq.gz | Fastqsanger.gz | |||
| SRR7281223.fastq.gz | Fastqsanger.gz | |||
| SRR7281233.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:The role of Twist1 in mutant huntingtin-induced transcriptional alterations
2018-06-09 | GSE115523 | GEO
Project description:Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the huntingtin protein (Htt). Transcriptional dysregulation is an early event in the course of HD progression and is thought to contribute to disease pathogenesis, but how mutant Htt causes transcriptional alterations and subsequent cell death in neurons is not well understood. RNA-Seq analysis revealed that expression of a mutant Htt fragment in primary cortical neurons leads to robust gene expression changes before neuronal death. Basic helix-loop-helix transcription factor Twist1, which is essential for embryogenesis and is normally expressed at low levels in mature neurons, was substantially up-regulated in mutant Htt-expressing neurons in culture and in the brains of HD mouse models. Knockdown of Twist1 by RNAi in mutant Htt-expressing primary cortical neurons reversed the altered expression of a subset of genes involved in neuronal function and, importantly, abrogated neurotoxicity. Using brain-derived neurotrophic factor (Bdnf), which is known to be involved in HD pathogenesis, as a model gene, we found that Twist1 knockdown could reverse mutant Htt-induced DNA hypermethylation at the Bdnf regulatory region and reactivate Bdnf expression. Together, these results suggest that Twist1 is an important upstream mediator of mutant Htt-induced neuronal death and may in part operate through epigenetic mechanisms.
| S-EPMC6066321 | biostudies-literature
Project description:Twist1 variants including wildtype Twist1, a non-phosphorylatable mutant Twist1/S42A and a phospho-mimicking mutant Twist1/S42D were expressed in 4T1 cells in which the endogenous Twist1 was depleted. We wanted to use microarray analysis to evaluate those genes that are differentially regulated by Twist1 variants.
2012-05-01 | GSE29754 | GEO
Project description:The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin
| PRJNA408232 | ENA
Project description:Twist1 variants including wildtype Twist1, a non-phosphorylatable mutant Twist1/S42A and a phospho-mimicking mutant Twist1/S42D were expressed in 4T1 cells in which the endogenous Twist1 was depleted. We wanted to use microarray analysis to evaluate those genes that are differentially regulated by Twist1 variants. All cell lines were grown to 70% confluency and total RNA was isolated with Qiagen kit. Each sample was prepared as triplicates. Parental 4T1 cells were used as control.
2012-04-30 | E-GEOD-29754 | biostudies-arrayexpress
Project description:TWIST1 is known to play a role in the metastatic progression of melanoma. However, the range of TWIST1 targets is poorly charachterized. Here microarray analysis was used to define the TWIST1 regulated transcriptome in the human melanoma cell line WM793.
2019-04-03 | GSE128955 | GEO
Project description:The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (Doublecortin-like kinase 3) which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington's disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodeling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including TADA3, a core component of SAGA complex. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodeling in these brain cells, and show that reduced expression of the kinase in Huntington’s disease could render the striatum highly vulnerable to neurodegeneration. Examination of DCLK3 as neuroprotector against mutant huntingtin in vivo and in vitro models.
2018-03-22 | GSE104091 | GEO
Project description:The mechanisms involved in the pathogenesis of HD that result in late, and fatal, neurodegeneration are still not fully understood. The monogenic nature of HD is in contradiction with the complexity of the cellular alterations found in patients with HD. Huntingtin interacts with a broad range of proteins within the cell, and it is altered by the expanded polyglutamine tract. Transcriptional dysregulation is a common finding in genetic models and in human HD patients, and it is thought to play an important role in the disease. Although the onset of the disease is late in life, growing lines of evidence suggest that mHtt causes alterations in development. In this microarray study, the effects of mHtt on the transcriptome were investigated with a full-length human huntingtin (96 CAG repeats) expressing transgenic rat model of HD at an early stage of development (E14).
2014-11-30 | GSE63295 | GEO
Project description:Non-small cell lung carcinoma (NSCLC) is a major cause of cancer mortality. High expression of the epithelial-to-mesenchymal transition transcription factor (EMT-TF) Twist1 is strongly associated with metastatic cancers and with treatment resistance. Twist1 can also upregulate O-GlcNAcylation to suppress fail-safe programs such as KrasG12D oncogene-induced senescence (OIS) that accelerates NSCLC tumorigenesis. We wanted to decipher the critical domains and transcriptional targets required for Twist1 acceleration of lung tumorigenicity. We created a novel genetically-engineered mouse model for autochthonous lung cancer through lung epithelial expression of KrasG12D oncogene (CR) concomitantly with Twist1wt (CRT) or a Twist1F191G transactivation-null mutant (CRF191G). Compared to CR and CRF191G, CRT mice had shorter tumor-free survival and more aggressive tumors histologically. CRT lung tumors also showed higher proliferation and lower cell-cycle arrest suggesting that the Twist1 transactivation-domain is important for OIS suppression. Supporting these data, we observed in non-cancer human bronchial epithelial cells (HBECs) that the co-expression of human TWIST1wt enhanced tumorigenic/invasive programs and could suppress HRasG12V-induced senescence while co-expressing TWIST1F187G transactivation-null mutant could not. TWIST1wt co-expression with HRasG12V in HBECs differentially modulated MYC downstream transcriptional programs. Finally, OIS induction in HBEC-HRasG12V-TWIST1wt was rescued by O-GlcNAcylation inhibition or by treatment with a novel MYC inhibitor MYCi975. Altogether, these results indicate that the Twist1 transactivation domain is required for Twist1-dependent acceleration of lung tumorigenesis via MYC and nominate MYCi975 as a means to activate latent OIS programs. MYC targeting strategies could limit pro-tumorigenic programs and serve as a therapeutic for TWIST1-overexpressing NSCLCs.
2024-12-01 | GSE270902 | GEO