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Modulation of mitochondrial DNA copy number in a model of glioblastoma induces changes to DNA methylation and gene expression of the nuclear genome in tumours.

ABSTRACT: BACKGROUND:There are multiple copies of mitochondrial DNA (mtDNA) present in each cell type, and they are strictly regulated in a cell-specific manner by a group of nuclear-encoded mtDNA-specific replication factors. This strict regulation of mtDNA copy number is mediated by cell-specific DNA methylation of these replication factors. Glioblastoma multiforme, HSR-GBM1, cells are hyper-methylated and maintain low mtDNA copy number to support their tumorigenic status. We have previously shown that when HSR-GBM1 cells with 50% of their original mtDNA content were inoculated into mice, tumours grew more aggressively than non-depleted cells. However, when the cells possessed only 3% and 0.2% of their original mtDNA content, tumour formation was less frequent and the initiation of tumorigenesis was significantly delayed. Importantly, the process of tumorigenesis was dependent on mtDNA copy number being restored to pre-depletion levels. RESULTS:By performing whole genome MeDIP-Seq and RNA-Seq on tumours generated from cells possessing 100%, 50%, 0.3% and 0.2% of their original mtDNA content, we determined that restoration of mtDNA copy number caused significant changes to both the nuclear methylome and its transcriptome for each tumour type. The affected genes were specifically associated with gene networks and pathways involving behaviour, nervous system development, cell differentiation and regulation of transcription and cellular processes. The mtDNA-specific replication factors were also modulated. CONCLUSIONS:Our results highlight the bidirectional control of the nuclear and mitochondrial genomes through modulation of DNA methylation to control mtDNA copy number, which, in turn, modulates nuclear gene expression during tumorigenesis.

SUBMITTER: Sun X

PROVIDER: S-EPMC6136172 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Modulation of mitochondrial DNA copy number in a model of glioblastoma induces changes to DNA methylation and gene expression of the nuclear genome in tumours.

Sun Xin X St John Justin C JC

Epigenetics & chromatin 20180912 1

<h4>Background</h4>There are multiple copies of mitochondrial DNA (mtDNA) present in each cell type, and they are strictly regulated in a cell-specific manner by a group of nuclear-encoded mtDNA-specific replication factors. This strict regulation of mtDNA copy number is mediated by cell-specific DNA methylation of these replication factors. Glioblastoma multiforme, HSR-GBM1, cells are hyper-methylated and maintain low mtDNA copy number to support their tumorigenic status. We have previously sho ...[more]

PMID: 30208958

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Project description:BACKGROUND:Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. METHODS:To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N?=?533) and Framingham Heart Study (FHS) (N?=?1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. RESULTS:Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P?<?5?×?10-?8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P?<?5?×?10-?8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P?=?5.24?×?10-?12), as well as the TFAM knockout methylation (P?= 4.41?×?10-?4) and expression (P?= 4.30?×?10-?4) studies. CONCLUSIONS:These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most severe cancers and is characterized by chemotherapy resistance and poor prognosis associated with epithelial-mesenchymal transition (EMT). In a previous study, a low mitochondrial DNA (mtDNA) copy number was associated with poorer prognosis and induced EMT in ESCC. However, the detailed mechanism related to mtDNA copy number and EMT is unclear. The aim of this study was to clarify the mechanism by which a change in mtDNA copy number contributes to EMT and to examine treatment of chemotherapy resistance in ESCC.MethodsThe association between low mtDNA copy number and chemotherapy resistance was investigated using specimens from 88 patients who underwent surgery after neoadjuvant chemotherapy. Then, the mtDNA content of human ESCC cell lines, TE8 and TE11, was depleted by knockdown of mitochondrial transcription factor A expression. The present study focused on modulation of mitochondrial membrane potential (MMP) and DNA methylation as the mechanisms by which mtDNA copy number affects EMT. mRNA and protein expression, chemotherapy sensitivity, proliferation, MMP and DNA methylation were evaluated, and in vitro and in vivo assays were conducted to clarify these mechanisms.ResultsESCC patients with decreased mtDNA copy number who underwent R0 resection after neoadjuvant chemotherapy had significantly worse pathological response and recurrence-free survival. Additionally, low mtDNA copy number was associated with resistance to chemotherapy in vitro and in vivo. mtDNA controlled MMP, and MMP depolarization induced EMT. Depletion of mtDNA and low MMP induced DNA methylation via a DNA methylation transcription factor (DNMT), and a DNMT inhibitor suppressed EMT and improved chemotherapy sensitivity in mtDNA-depleted ESCC cells, as shown by in vitro and in vivo assays.ConclusionThis study showed that decreased mtDNA copy number induced EMT via modulation of MMP and DNA methylation in ESCC. Therapeutic strategies increasing mtDNA copy number and DNMT inhibitors may be effective in preventing EMT and chemosensitivity resistance.

Dataset Information

Modulation of mitochondrial DNA copy number in a model of glioblastoma induces changes to DNA methylation and gene expression of the nuclear genome in tumours.

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Modulation of mitochondrial DNA copy number in a model of glioblastoma induces changes to DNA methylation and gene expression of the nuclear genome in tumours.

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