Evidence map›Paper›PMID 25719248›Full record

ArticleCell death & disease2015

Mitochondrial DNA copy number is regulated by DNA methylation and demethylation of POLGA in stem and cancer cells and their differentiated progeny.

W Lee, J Johnson, D J Gough, J Donoghue, G L M Cagnone, V Vaghjiani, K A Brown, T G Johns, J C St John

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell death & disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
64citing papers in PubMed, 2 pooled it
6.5field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

64 citing papers in PubMed, 2 syntheses or guidelines pooled it, 130 citations in OpenAlex.

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4 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 3 institutions in 1 country.

W Lee1] Centre for Genetic Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
J Johnson1] Centre for Genetic Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
D J Gough1] Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
J Donoghue1] Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
G L M Cagnone1] Centre for Genetic Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
V Vaghjiani1] Centre for Genetic Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
K A Brown1] Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
T G Johns1] Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
J C St John1] Centre for Genetic Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia [2] Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
Monash University · AUHudson Institute of Medical Research · AUMonash Institute of Medical Research · AU

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation so that cells with a high requirement for ATP generated through oxidative phosphorylation have high mtDNA copy number, whereas those with a low requirement have few copies. Using immunoprecipitation of DNA methylation on 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), which distinguish between de novo DNA methylation and demethylation, respectively, we set out to determine whether DNA methylation at exon 2 of the human mtDNA-specific polymerase (DNA polymerase gamma A (POLGA)) regulates cell-specific mtDNA copy number in highly proliferative and terminally differentiated cells. Highly proliferative cancer and pluripotent and multipotent cells possessed low mtDNA copy number and were highly methylated at exon 2 of POLGA in contrast to post-mitotic cells. Unlike neural stem cells, cancer cells were unable to differentiate and remained extensively DNA methylated at exon 2 of POLGA. However, mtDNA depletion of cancer cells reduced DNA methylation at exon 2 of POLGA as they replenished mtDNA to form tumours in mice. Glioblastoma cells treated with the DNA demethylation agent 5-azacytidine over 28 days of astrocyte-induced differentiation demethylated exon 2 of POLGA leading to increased mtDNA copy number and expression of the astrocyte endpoint marker glial fibrillary acidic protein (GFAP). However, the demethylation agent vitamin C (VitC) was unable to sustain increased mtDNA copy number and differentiation, as was the case when VitC was withdrawn after short-term treatment. These data demonstrate that DNA demethylation of POLGA is an essential regulator of mtDNA copy number and cellular fate and that cancer cells are only able to modulate DNA methylation of POLGA and mtDNA copy number in the presence of a DNA demethylation agent that inhibits de novo methyltransferase 1 activity.

Indexed as

Ascorbic AcidAzacitidineBlotting, WesternCell DifferentiationCell LineCell Line, TumorChromatin ImmunoprecipitationDNA Copy Number VariationsDNA-Directed DNA PolymeraseDNA MethylationDNA, MitochondrialDNA Polymerase gammaHumansImmunoprecipitationReal-Time Polymerase Chain ReactionAscorbic AcidAzacitidineDNA-Directed DNA PolymeraseDNA, MitochondrialDNA Polymerase gammaPOLG protein, human

Identifiers

PMID25719248
PMCPMC4669800
OpenAlexW1970857726

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.