Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs

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 expre...

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Veröffentlicht in:	Genome medicine Jg. 12; H. 1; S. 84 - 17
Hauptverfasser:	Castellani, Christina A., Longchamps, Ryan J., Sumpter, Jason A., Newcomb, Charles E., Lane, John A., Grove, Megan L., Bressler, Jan, Brody, Jennifer A., Floyd, James S., Bartz, Traci M., Taylor, Kent D., Wang, Penglong, Tin, Adrienne, Coresh, Josef, Pankow, James S., Fornage, Myriam, Guallar, Eliseo, O’Rourke, Brian, Pankratz, Nathan, Liu, Chunyu, Levy, Daniel, Sotoodehnia, Nona, Boerwinkle, Eric, Arking, Dan E.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London BioMed Central 28.09.2020 BioMed Central Ltd Springer Nature B.V BMC
Schlagworte:	African Americans Aging Analysis Arteriosclerosis Atherosclerosis Bioinformatics Biomedical and Life Sciences Biomedicine Blood Brain research Cancer Research Cardiovascular disease Cardiovascular diseases Cardiovascular Diseases - genetics Cardiovascular Diseases - mortality Copy number Coronary artery disease Coronary heart disease CpG Islands CRISPR Cross-Sectional Studies Deoxyribonucleic acid Disease Susceptibility DNA DNA Copy Number Variations DNA Methylation DNA, Mitochondrial DNA-Binding Proteins - genetics Efficiency Enzymes Epigenomics Gene Expression Gene Knockdown Techniques Genes Genetic research Genome-Wide Association Study Genomes Genomics Health aspects Heart diseases Human Genetics Humans Medicine/Public Health Metabolomics Methylation Mitochondria Mitochondria - genetics Mitochondrial DNA Mitochondrial Proteins - genetics Mortality Odds Ratio Phenotype Phenotypes Polymorphism, Single Nucleotide Prognosis Quality control Quantitative Trait Loci Signal Transduction Stem cells Systems Biology Transcription Factors - genetics United States > US Cardiovascular disease Mitochondrial DNA Epigenomics Mortality
ISSN:	1756-994X, 1756-994X
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1756-994X 1756-994X
DOI:	10.1186/s13073-020-00778-7