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The analysis of transcriptional profiles of cybrid cells harbouring two pathogenic mtDNA variants associated with Leigh syndrome

ABSTRACT: The analysis of transcriptional profiles of cybrid cells harbouring two pathogenic mtDNA variants associated with Leigh syndrome

PROVIDER: PRJEB48089 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR7051210.fastq.gz	Fastqsanger.gz
	ERR7051220.fastq.gz	Fastqsanger.gz
	ERR7051211.fastq.gz	Fastqsanger.gz
	ERR7051221.fastq.gz	Fastqsanger.gz
	ERR7051212.fastq.gz	Fastqsanger.gz

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The analysis of transcriptional profiles of cybrid cells harbouring two pathogenic mtDNA variants associated with Leigh syndrome

Project description:The analysis of transcriptional profiles of cybrid cells harbouring two pathogenic mtDNA variants associated with Leigh syndrome i.e., m.9185T>C in the mt-ATP6 gene and m.13513G>A in the mt-ND5 gene, in comparison to cybrid cells harbouring control mtDNA haplogroups or the wt m.13513G variant.

2023-04-01 | E-MTAB-11035 | biostudies-arrayexpress

Genetic Correction and Metabolic Rescue of Pluripotent Cells from Patients with mtDNA

Project description:Mitochondria are vital due to their principal role in energy production via oxidative phosphorylation (OXPHOS)1. Mitochondria carry their own genome (mtDNA) encoding critical genes involved in OXPHOS, therefore, mtDNA mutations cause fatal or severely debilitating disorders with limited treatment options. 2. Clinical manifestations of mtDNA disease vary based on mutation type and heteroplasmy levels i.e. presence of mutant and normal mtDNA within each cell. 3,4. We evaluated therapeutic concepts of generating genetically corrected pluripotent stem cells for patients with mtDNA mutations. We initially generated multiple iPS cell lines from a patient with mitochondrial encephalomyopathy and stroke-like episodes (MELAS) caused by a heteroplasmic 3243A>G mutation and a patient with Leigh disease carrying a homoplasmic 8993T>G mutation (Leigh-iPS). Due to spontaneous mtDNA segregation in proliferating fibroblasts, isogenic MELAS iPS cell lines were recovered containing exclusively wild type (wt) mtDNA with normal metabolic function. As expected, all iPS cells from the patient with Leigh disease were affected. Using somatic cell nuclear transfer (SCNT; Leigh-NT1), we then simultaneously replaced mutated mtDNA and generated pluripotent stem cells from the Leigh patient fibroblasts. In addition to reversing to a normal 8993G>T, oocyte derived donor mtDNA (human haplotype D4a) in Leigh-NT1 differed from the original haplotype (F1a) at a additional 47 nucleotide sites. Leigh-NT1 cells displayed normal metabolic function compared to impaired oxygen consumption and ATP production in Leigh-iPS cells or parental fibroblasts (Leigh-fib). We conclude that natural segregation of heteroplasmic mtDNA allows the generation of iPS cells with exclusively wild type mtDNA. Moreover, SCNT offers mitochondrial gene replacement strategy for patients with homoplasmic mtDNA disease.

2015-07-16 | GSE61390 | GEO

Pathogenic mtDNA mutations inhibit melanoma metastasis

Project description:We report the transcriptome profiles of A375 melanoma tumors containing distinct mtDNA mutations. This study was performed using subcutaneous tumors implanted into NSG mice, and identifies transcriptomice changes in response to pathogenic mtDNA mutations.

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Pathogenic mtDNA mutations inhibit melanoma metastasis

Project description:Pathogenic mtDNA mutations inhibit melanoma metastasis

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Elucidation of the expression profile of independent clones of mutant mtBALB and wild type control mtB6 murine cybrid cells

Project description:We generated murine fibroblast cybrid cell lines that have identical nuclear genomes and differ only in their mtDNA. We observed increased cellular proliferation and resistance to apoptosis in the mtBALB compared to the mtB6 cybrid cells, phenotypes seen in malignant cells. Based on these observations we investigated whether these phenotypic differences could be caused by a unique spectrum of nuclear gene expression alterations induced by the mtDNA changes. Microarray analysis (Agilent, 44K mouse whole genome chip) was conducted in order to elucidate the expression profile of three independent clones of mtBALB and mtB6 cybrid cells. Two-condition experiment, mtB6 vs. mtBALB cells. Biological replicates: 4 control replicates, 4 mutant replicates.

2012-06-25 | E-GEOD-21855 | biostudies-arrayexpress

Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for precise termination of mtDNA replication

Project description:The exact in vivo role for RNase H1 in mammalian mitochondria (mtDNA) has been much debated and we show here that it is essential for processing of RNA primers to provide site-specific initiation of mtDNA replication. Without RNase H1, mtDNA replication is instead initiated at non-canonical sites and becomes impaired. Furthermore, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain (HBD) of RNase H1 causing impaired mtDNA replication. In contrast to catalytically dead pathological variants of RNase H1, this mutant version has enhanced enzyme activity. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.

2022-07-13 | GSE199198 | GEO

Elucidation of the expression profile of independent clones of mutant mtBALB and wild type control mtB6 murine cybrid cells

2012-06-26 | GSE21855 | GEO

ChIP analysis trial of human TFB2M and POLRMT interaction with mtDNA

Project description:In many mammalian tissues and cells, two classes of mitochondrial DNA (mtDNA) replication intermediates have been observed. One involves leading-strand synthesis in the absence of synchronous lagging-strand synthesis (strand-asynchronous replication), and the other has properties of coupled leading- and lagging-strand synthesis (strand-coupled replication). While strand-asynchronous replication is primed by long RNA synthesized from a defined transcription initiation site, little is known about the commencement of strand-coupled replication. To investigate it, we attempted to abolish strand-asynchronous replication in cultured human cybrid cells by knocking out the components of the transcription initiation complexes, mitochondrial transcription factor B2 (TFB2M/mtTFB2) and mitochondrial RNA polymerase (POLRMT/mtRNAP). Surprisingly, removal of either protein resulted in the complete mtDNA loss, demonstrating for the first time that TFB2M and POLRMT are indispensable for human mtDNA maintenance. Moreover, the lack of TFB2M could not be compensated for by mitochondrial transcription factor B1 (TFB1M/mtTFB1). These findings indicate that TFB2M and POLRMT are crucial for the priming of not only strand-asynchronous but also strand-coupled replication, providing deeper insights into the molecular basis of strand-coupled replication initiation.

2021-11-21 | GSE161542 | GEO

Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for precise termination of mtDNA replication

Project description:The exact in vivo role for RNase H1 in mammalian mitochondria has been much debated and we show here that it is essential for site-specific formation of RNA primers to allow initiation of mtDNA replication. Without RNase H1, the RNA:DNA hybrids at the replication origins are not processed and mtDNA replication is instead initiated at non-canonical sites and becomes impaired. Furthermore, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain (HBD) of RNase H1 causing impaired mtDNA replication. In contrast to catalytically dead pathological variants of RNase H1, this mutant version has enhanced enzyme activity. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.

2022-08-16 | GSE199771 | GEO

Expression data from cytoplasmic hybrid (cybrid) and rho0 cells

Project description:Mitochondria have been implicated in insulin resistance and beta cell dysfunction, both of which comprise the core pathophysiology of type 2 diabetes mellitus (T2DM). It has also recently been found that mtDNA haplogroups are distinctively associated with susceptibility to T2DM at least in Koreans and Japanese. To investigate the functional consequences of different mtDNA, we compared gene expression profiles between cybrid clones harboring three different mtDNA haplogroups (D5, F, and N9a). To produce hybrid clones, we fused mtDNA-depleted osteosarcoma cell line (143B TK- rho0) with nucleus-lacking platelets from twelve donors harboring the three haplogroups. A total of twelve cybrid clones from the three mtDNA haplogroups were obtained: D5 (n=3), F (n=5), and N9a (n=4). For each clone, four technical replicates were obtained and hybridized to the array. For rho0 cell, six technical replicates were obtained and hybridized to the array.

2012-03-31 | E-GEOD-26244 | biostudies-arrayexpress

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