ChIP-seq analysis of 143B cells upon mtDNA depletion and metabolic intervention [ChIP-Seq 2]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA521113 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8538400_1.fastq.gz | Fastqsanger.gz | |||
| SRR8538400_2.fastq.gz | Fastqsanger.gz | |||
| SRR8538391_1.fastq.gz | Fastqsanger.gz | |||
| SRR8538391_2.fastq.gz | Fastqsanger.gz | |||
| SRR8538401_1.fastq.gz | Fastqsanger.gz |
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Project description:The mitochondrial protein repertoire varies depending on cellular states, tissue type, species, and disease state. However, little is known about how this repertoire changes under different cellular or disease states. To gain a better understanding of dynamic mitochondrial proteomic changes, we compared alterations of mitochondrial proteome with transcriptome under mitochondrial DNA depletion. Total RNA obtained from 143B TK- osteosarcoma ?+ cells or 143B TK- osteosarcoma ?° cells
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Project description:Gene expression analysis upon mtDNA depletion
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Project description:Mitochondria generate signals of adaptation that regulate nuclear genes expression via retrograde signaling. But this phenomenon is complexified when qualitatively different mitochondria and mitochondrial DNA (mtDNA) coexist within cells. Although this cellular state of heteroplasmy leads to divergent phenotypes clinically, its consequences on cellular function and the cellular transcriptome are unknown. To interrogate this phenomenon, we generated somatic cell cybrids harboring increasing levels of a common mtDNA mutation (tRNALeu(UUR) 3243A>G) and mapped the resulting cellular phenotypes and transcriptional profiles across the complete range of heteroplasmy. Small increases in mutant mtDNAs caused relatively modest defect in mitochondrial oxidative capacity, but resulted in sharp transitions in mitochondrial ultrastructure and in the nuclear and mitochondrial transcriptomes, with the critical functional threshold corresponding to the induction of epigenetic regulatory systems. Principal component analysis underscores how each heteroplasmy level occupies a different "transcriptional space", with low levels heteroplasmy (20-30%) producing a dose-response linear progression in one direction, and mutationload of 50, 60 and 90% producing changes in the opposite direction. Hence, subtle changes in mitochondrial energetics can act through the epigenome to generate the phenotypes of the common “complex” diseases. Cells were generated by transferring the wildtype (3243A) and mutant (3243G) mtDNAs from a heteroplasmic 3243A>G patient’s lymphoblastoid cell line into 143B(TK-) mtDNA-deficient (ρo) cells and selected for transmitochondrial cybrids. Subsequent mtDNA depletion, reamplification, and cloning (Wiseman and Attardi, 1978) resulted in a series of stable cybrids harboring approximately 0, 20, 30, 50, 60, 90, and 100% 3243G mutant mtDNAs. Total RNA extracted from each cell line was then extracted, depleted of rRNA, and measured in sequenced in triplicates.
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