Dataset Information

Systemic transcriptome alternation under mtDNA depletion in 143B TK- osteosarcoma cells

ABSTRACT: 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 ρ+ cells or 143B TK- osteosarcoma ρ° cells

ORGANISM(S): Homo sapiens

SUBMITTER: hyun-jung koo Youngmi K Pak Hyun-Jung Koo

PROVIDER: E-GEOD-22970 | ArrayExpress | 2010-07-17

SECONDARY ACCESSION(S): GSE22970PRJNA127745

REPOSITORIES: GEO, ArrayExpress

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Project description:The goal of the study was to understand whether mitochondrial-driven epigenetic changes regulate gene expression. Mitochondrial metabolism has been implicated in epigenetics but the extent to which this impacts gene expression is unclear. Here we show that loss of mitochondrial DNA (mtDNA) results in locus-specific alterations in histone acetylation, DNA methylation and expression of a subset of genes. Most of these changes are rescued by restoring mitochondrial electron transport in a way that maintains the oxidative tricarboxylic acid cycle, but not reactive oxygen species or ATP production, or by modulating the mitochondrial pool of acetyl-CoA. Changes in acetyl-CoA and histone acetylation precede overt mitochondrial dysfunction and significant changes in gene expression and DNA methylation. This suggests that acetyl-CoA levels signal mitochondrial status to the nucleus. Differentially expressed genes with altered histone marks or DNA methylation regulate amino acid degradation, which likely compensates for the changes in acetyl-CoA and one carbon metabolism. These have the potential to further affect methylation reactions, redox control and nucleotide levels. These results illustrate the extent to which mitochondria impact cell physiology through epigenetic remodeling. Overall design: We analyzed HEK293 cells in which mtDNA was depleted by doxycycline addition to the medium to turn a dominant negative mitochondrial DNA polymerase (DN-POLG). Samples were analyzed at days 0, 3, 6 and 9 for a total of 4 samples. Each time point was done in three indepedent biological replicates. Time point 0 was used as controls with samples being un-induced. To determine the TCA cycles effects, HEK293 DN-POLG overexpressing AOX/NDI1 were also included at days 0 and 9, with 3 biological replicates to each Gene expression was also evaluated in 143B cells in which mtDNA was chronically depleted based on ethidium bromide treatment. Samples include 3 independent biological replicates of controls (rho+) and 3 of mtDNA depleted (rho0).

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