*Result*: Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
Title:
Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
Authors:
Win PW; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada., Nguyen J; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada., Shin EH; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada., Nagano TS; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada., Selimi B; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada., Hong K; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Meybodi AM; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada., Yates BP; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Burke EV; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Carter DE; London Regional Genomics Centre, Robarts Research Institute, London, Ontario, Canada., Newby GA; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.; Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA.; Department of Molecular Biology and Genetics, Johns Hopkins University, Baltimore, MD, USA., Newcomb C; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Arking DE; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Castellani CA; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.; Children's Health Research Institute, Lawson Research Institute, London, Ontario, Canada.
Source:
Epigenomics [Epigenomics] 2026 Jan; Vol. 18 (1), pp. 27-44. Date of Electronic Publication: 2025 Dec 23.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Taylor & Francis Country of Publication: England NLM ID: 101519720 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1750-192X (Electronic) Linking ISSN: 1750192X NLM ISO Abbreviation: Epigenomics Subsets: MEDLINE
Imprint Name(s):
Publication: 2024- : [Milton Park, Oxfordshire] : Taylor & Francis
Original Publication: London : Future Medicine, 2009-
Original Publication: London : Future Medicine, 2009-
MeSH Terms:
DNA, Mitochondrial*/genetics , Mitochondrial Proteins*/genetics , Transcription Factors*/genetics , DNA-Binding Proteins*/genetics , Cell Nucleus*/genetics , Epigenome* , DNA Copy Number Variations* , Transcriptome*, Humans ; DNA Methylation ; HEK293 Cells ; Epigenesis, Genetic ; Gene Knockout Techniques
Comments:
Update of: bioRxiv. 2024 Feb 10:2024.01.29.577835. doi: 10.1101/2024.01.29.577835.. (PMID: 38352513)
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Sci Rep. 2023 Nov 27;13(1):20914. (PMID: 38017005)
Genes Dev. 2012 May 1;26(9):877-90. (PMID: 22549953)
Am J Physiol Renal Physiol. 2023 Jul 1;325(1):F38-F49. (PMID: 37102686)
Environ Health Perspect. 2023 May;131(5):57703. (PMID: 37192320)
Biochim Biophys Acta. 2005 Mar 21;1733(1):29-52. (PMID: 15749056)
J Immunother Cancer. 2023 Mar;11(3):. (PMID: 36858460)
Hum Mol Genet. 2021 Dec 27;31(2):309-319. (PMID: 34415308)
Sci Rep. 2023 Jan 12;13(1):657. (PMID: 36635346)
Nat Genet. 1998 Mar;18(3):231-6. (PMID: 9500544)
Diabetes Metab Syndr Obes. 2015 Feb 03;8:79-87. (PMID: 25678807)
Bioinformatics. 2017 Feb 15;33(4):558-560. (PMID: 28035024)
Nucleic Acids Res. 2000 Jan 1;28(1):27-30. (PMID: 10592173)
JAMA Cardiol. 2017 Nov 1;2(11):1247-1255. (PMID: 29049454)
Clin Sci (Lond). 2016 Aug 1;130(15):1285-305. (PMID: 27358026)
Am J Transl Res. 2018 May 15;10(5):1444-1456. (PMID: 29887958)
Epigenetics Chromatin. 2018 Sep 12;11(1):53. (PMID: 30208958)
Mol Biosyst. 2016 Feb;12(2):477-9. (PMID: 26661513)
Clin Epigenetics. 2021 Mar 22;13(1):60. (PMID: 33752734)
Elife. 2016 Feb 22;5:. (PMID: 26901439)
Cell Metab. 2012 Dec 5;16(6):765-76. (PMID: 23168219)
Epigenomes. 2020 Sep 01;4(3):. (PMID: 34968291)
Int J Mol Med. 2022 Aug;50(2):. (PMID: 35713211)
Cell Death Dis. 2015 Apr 02;6:e1710. (PMID: 25837486)
Nature. 2016 Nov 17;539(7629):390-395. (PMID: 27799657)
Trends Mol Med. 2011 Aug;17(8):452-62. (PMID: 21514225)
Med Res Rev. 2020 Nov;40(6):2485-2565. (PMID: 32691504)
Neurogenetics. 2006 Jul;7(3):167-74. (PMID: 16770606)
FEBS Lett. 2021 Apr;595(8):976-1002. (PMID: 33314045)
Cancer Biol Ther. 2008 Aug;7(8):1182-90. (PMID: 18458531)
Grant Information:
R00 HL163805 United States HL NHLBI NIH HHS; R01 HL144569 United States HL NHLBI NIH HHS
Contributed Indexing:
Keywords: Mitochondria; epigenome; mitochondrial DNA; mitochondrial DNA copy number; transcriptome
Local Abstract: [plain-language-summary] The amount of mitochondrial DNA, called mitochondrial DNA copy number (mtDNA-CN), has been linked with risk for various health conditions and diseases. To better understand this relationship, we studied the association between mtDNA-CN reduction and other DNA changes within the cell, specifically those in the cell nucleus. Using a cell model, we compared changes in cells with lower mtDNA-CN to normal cells. We noticed several patterns of changes that point to different genomic regions, communication processes, and signaling pathways within the cells that may be involved in the association of mtDNA-CN with disease development. Our findings help explain how the mitochondria interact with the nucleus in the context of complex disease.
Local Abstract: [plain-language-summary] The amount of mitochondrial DNA, called mitochondrial DNA copy number (mtDNA-CN), has been linked with risk for various health conditions and diseases. To better understand this relationship, we studied the association between mtDNA-CN reduction and other DNA changes within the cell, specifically those in the cell nucleus. Using a cell model, we compared changes in cells with lower mtDNA-CN to normal cells. We noticed several patterns of changes that point to different genomic regions, communication processes, and signaling pathways within the cells that may be involved in the association of mtDNA-CN with disease development. Our findings help explain how the mitochondria interact with the nucleus in the context of complex disease.
Substance Nomenclature:
0 (DNA, Mitochondrial)
0 (TFAM protein, human)
0 (Mitochondrial Proteins)
0 (Transcription Factors)
0 (DNA-Binding Proteins)
0 (TFAM protein, human)
0 (Mitochondrial Proteins)
0 (Transcription Factors)
0 (DNA-Binding Proteins)
Entry Date(s):
Date Created: 20251223 Date Completed: 20260116 Latest Revision: 20260125
Update Code:
20260130
PubMed Central ID:
PMC12826749
DOI:
10.1080/17501911.2025.2603883
PMID:
41431444
Database:
MEDLINE
*Further Information*
*Aims: Mitochondrial DNA copy number (mtDNA-CN) is associated with several age-related chronic diseases and is a predictor of all-cause mortality. Here, we examine site-specific differential nuclear DNA (nDNA) methylation and differential gene expression resulting from in vitro reduction of mtDNA-CN to uncover shared genes and biological pathways mediating the effect of mtDNA-CN on disease.
Materials and Methods: Epigenome and transcriptome profiles were generated for three independent human embryonic kidney (HEK293T) cell lines harboring a mitochondrial transcription factor A (TFAM) knockout generated via CRISPR-Cas9, and matched control lines.
Results: We identified 2924 differentially methylated sites, 67 differentially methylated regions, and 102 differentially expressed genes associated with mtDNA-CN. Integrated analysis uncovered 24 Gene-CpG pairs. GABA<subscript>A</subscript> receptor genes and related pathways, the neuroactive ligand signaling pathway, ABCD1/2 gene activity, and cell signaling processes were overrepresented, providing insight into the underlying biological mechanisms facilitating these associations. We also report evidence implicating chromatin state regulatory mechanisms as modulators of mtDNA-CN effect on gene expression.
Conclusions: We demonstrate that mitochondrial DNA variation signals to the nuclear DNA epigenome and transcriptome and may lead to nuclear remodeling relevant to development, aging, and complex disease.*