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A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial-temporal regulation of histone arginine methylation in neurodevelopment

ABSTRACT: A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial-temporal regulation of histone arginine methylation in neurodevelopment

PROVIDER: PRJNA851462 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19774946_1.fastq.gz	Fastqsanger.gz
	SRR19774946_2.fastq.gz	Fastqsanger.gz
	SRR19774947_1.fastq.gz	Fastqsanger.gz
	SRR19774947_2.fastq.gz	Fastqsanger.gz
	SRR19774948_1.fastq.gz	Fastqsanger.gz

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A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial-temporal regulation of histone arginine methylation in neurodevelopment

Project description:We report a loss-of-function mutation in the TLDc domain of human Oxidation Resistance 1 (OXR1) gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generated patient derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identified that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1 dependent mechanisms regulating gene expression during neurodevelopment. We modeled the function of OXR1 in early human brain development using patient derived brain organoids revealing that OXR1 contributes to the spatial-temporal regulation of histone arginine methylation in specific brain regions. Our work provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency, highlighting the therapeutic potential of OXR1 in numerous neurodegenerative and neurodevelopmental disorders.

2023-04-06 | GSE206614 | GEO

A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial-temporal regulation of histone arginine methylation in neurodevelopment.

Project description:BackgroundOxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency.ResultsWe report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial-temporal regulation of histone arginine methylation in specific brain regions.ConclusionsThis study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.

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5-hydroxymethylcytosine-mediated epigenetic dynamics during neurodevelopment and aging

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Project description:DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base derived from 5-methylcytosine (5mC) accounts for ~40% of modified cytosine in brain, and has been implicated in DNA methylation-related plasticity. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We find developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC-regulated regions reveals stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by finding that its levels are inversely correlated with methyl-CpG-binding protein 2 (Mecp2) dosage, a protein encoded by a gene in which mutations cause Rett Syndrome. These data point toward critical roles for 5-hmC-mediated epigenetic modification in neurodevelopment and diseases. Gene expression data derived from P7 and 6wk mouse cerebellum used for determining expression outcomes associated with dynamic alterations in 5-hydroxymethylcytosine

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Chromatin accessibility governs the differential response of cancer and T-cells to arginine starvation (Illumina HumanHT-12 V4.0 beadchip)

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