Analysis on the transcriptomic profile in the cerebellar vermis of ataxia telangiectasia patients
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ABSTRACT:
PROVIDER: PRJNA733518 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14682544_1.fastq.gz | Fastqsanger.gz | |||
| SRR14682544_2.fastq.gz | Fastqsanger.gz | |||
| SRR14682545_1.fastq.gz | Fastqsanger.gz | |||
| SRR14682545_2.fastq.gz | Fastqsanger.gz | |||
| SRR14682546_1.fastq.gz | Fastqsanger.gz |
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Project description:Cerebellar cortex expression in ataxia-telangiectasia patients and normal controls. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency. Human frozen tissue was obtained from the NICHD Brain and Tissue Bank of Developmental Disorders at the University of Maryland, Baltimore, MD. RNA was prepared and run on an Illumina Human HT-12 v4 microarray. 3 ataxia-telangiectasia (A-T) cases and 4 normal controls.
2015-10-30 | E-GEOD-61019 | biostudies-arrayexpress
Project description:Previous studies have demonstrated the possible roles of dysregulation of endogenous retroelements in the pathogenesis of neurodegenerative diseases. In our study, we demonstrated that the activation and upregulation of endogenous retroelement LINE-1 in the cerebellum can induce the cerebellar ataxia phenotype in vivo using mouse model. While there has been reports demonstrating that ATM gene, whose mutations are causative of Ataxia Telangiectasia (A-T) in humans, regulates LINE-1, and suggesting that the LINE-1 dysregulation caused by its mutation plays a role in the pathogenesis of ataxia phenotype in A-T, little is known about the transcriptome of the A-T patients’ cerebellum. This is the first detailed analysis of the cellular and retroelement transcriptome in A-T patient’s cerebellum, and the result of this analysis, together with the transcriptomic analysis in our LINE-1 activation mice, collectively suggests the profound roles of LINE-1 dysregulation in the development as well as the progression of ataxia in A-T patients.
2022-09-06 | GSE175776 | GEO
Project description:Cerebellar cortex expression in ataxia-telangiectasia patients and normal controls. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency.
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Project description:Analysis on the transcriptomic profile in NIH3T3 cells by LINE-1 overexpression with CRISPRa, and the cerebellar vermis of ataxia telangiectasia patients
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Project description:MicroRNA dysregulation in Ataxia Telangiectasia
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Project description:Control (CRL2429 C11) and A-T (MC3/AT30) iPSC were differentiated according to Erceg et al to generate cerebellar precursors
2017-10-02 | GSE75852 | GEO
Project description:Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+ reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+ also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.
2017-12-20 | GSE76380 | GEO
Project description:Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) samples
| EGAD00010000130 | EGA
Project description:Disease-specific induced pluripotent stem (iPS) cells have been used for a model to analyze pathogenesis of the disease. In this study, we generated iPS cells derived from a fibroblastic cell line of ataxia telangiectasia (AT-iPS cells), a neurodegenerative, inherited disease with chromosomal instability and hypersensitivity to ionizing radiation. AT-iPS cells exhibited hypersensitivity to X-ray irradiation, one of the characteristics of the disease. Surprisingly, while parental ataxia telangiectasia cells exhibited significant chromosomal abnormalities, AT-iPS cells did not show any chromosomal instability in vitro, i.e. maintenance of intact chromosomes at least by 80 passages (560 days) probably due to robust stability of pluripotent stem cells such as iPS cells and embryonic stem cells. The whole exome analysis also showed comparable nucleotide substitution speed in AT-iPS cells. Interestingly, after longer period of AT-iPS implantation into immunodeficient mice, teratoma generated by AT-iPS cells exhibited telangiectasia and carcinogenesis that are two characteristic symptoms of ataxia telangiectasia. Taken together, AT-iPS cells would be a good model for ataxia telangiectasia to clarify pathogenesis of the disease, and may allow us to facilitate development of drugs that inhibit ataxia and hypersensitivity to ionizing radiation for therapeutic application.
2013-06-22 | GSE47498 | GEO
Project description:Genomic DNA was prepared, fragmented, and immunoprecipitated with antibodies specific for 5mC or 5hmC prior to standard sequencing. The neurodegenerative disease known as ataxia-telangiectasia (A-T) is caused by the absence of the ATM (A-T mutated) protein. A long-standing mystery surrounding A-T is why cerebellar Purkinje cells (PCs) appear uniquely vulnerable to ATM-deficiency. Here, we present that 5-hydroxymethylcytosine (5hmC), a newly recognized epigenetic marker found at high levels in neurons, is substantially reduced in human A-T and Atm-/- mouse cerebellar PCs. TET1, an enzyme that converts 5mC to 5hmC, responds to DNA damage. Manipulation of TET1 activity directly affects neuronal cell cycle reentry and cell death after the induction of DNA damage. Quantitative, genome-wide analysis of 5hmC of samples from human cerebellum showed that in ATM-deficiency there is a remarkable genome-wide reduction of 5hmC enrichment at both proximal and distal regulatory elements. These results reveal a role of TET1-mediated 5hmC in DNA damage response, and provide insights into the basis of a PC-specific DNA demethylation alteration in ATM-deficiency. There are two groups, A-T and Control. For each group, cerebellar DNA samples were immunoprecipitated with anti-5mC (n=1) or anti-5hmC (n=3). There were also two replicates of input control for each group.
2015-10-30 | E-GEOD-61133 | biostudies-arrayexpress