Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs
Tóm tắt
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. 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. 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. 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.
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Tài liệu tham khảo
Clayton DA. Transcription and replication of animal mitochondrial DNAs. Int Rev Cytol. 1992;141:217–32.
Pello R, Martín MA, Carelli V, Nijtmans LG, Achilli A, Pala M, et al. Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum Mol Genet. 2008;17:4001–11.
Wai T, Ao A, Zhang X, Cyr D, Dufort D, Shoubridge EA. The role of mitochondrial DNA copy number in mammalian fertility. Biol Reprod. 2010;83:52–62.
Guha M, Avadhani NG. Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion. 2013;13:577–91.
Jeng J-Y, Yeh T-S, Lee J-W, Lin S-H, Fong T-H, Hsieh R-H. Maintenance of mitochondrial DNA copy number and expression are essential for preservation of mitochondrial function and cell growth. J Cell Biochem. 2008;103:347–57.
Dai D-F, Rabinovitch PS, Ungvari Z. Mitochondria and cardiovascular aging. Circ Res. 2012;110:1109–24.
Ashar FN, Zhang Y, Longchamps RJ, Lane J, Moes A, Grove ML, et al. Association of mitochondrial DNA copy number with cardiovascular disease. JAMA Cardiol. 2017;2:1247–55.
Chen S, Xie X, Wang Y, Gao Y, Xie X, Yang J, et al. Association between leukocyte mitochondrial DNA content and risk of coronary heart disease: a case-control study. Atherosclerosis. 2014;237:220–6.
Tin A, Grams ME, Ashar FN, Lane JA, Rosenberg AZ, Grove ML, et al. Association between mitochondrial DNA copy number in peripheral blood and incident CKD in the atherosclerosis risk in communities study. J Am Soc Nephrol. 2016;27:2467–73.
Ashar FN, Moes A, Moore AZ, Grove ML, Chaves PHM, Coresh J, et al. Association of mitochondrial DNA levels with frailty and all-cause mortality. J Mol Med. 2015;93:177–86.
Crovetto F, Lattuada D, Rossi G, Mangano S, Somigliana E, Bolis G, et al. A role for mitochondria in gestational diabetes mellitus? Gynecol Endocrinol. 2013;29:259–62.
Sookoian S, Rosselli MS, Gemma C, Burgueño AL, Fernández Gianotti T, Castaño GO, et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator–activated receptor γ coactivator 1α promoter. Hepatology. 2010;52:1992–2000.
Pirola CJ, Scian R, Gianotti TF, Dopazo H, Rohr C, Martino JS, et al. Epigenetic modifications in the biology of nonalcoholic fatty liver disease: the role of DNA hydroxymethylation and TET proteins. Medicine (Baltimore). 2015;94:e1480.
Delsite R, Kachhap S, Anbazhagan R, Gabrielson E, Singh KK. Nuclear genes involved in mitochondria-to-nucleus communication in breast cancer cells. Mol Cancer. 2002;1:6.
Kitamura E, Igarashi J, Morohashi A, Hida N, Oinuma T, Nemoto N, et al. Analysis of tissue-specific differentially methylated regions (TDMs) in humans. Genomics. 2007;89:326–37.
Horan MP, Cooper DN. The emergence of the mitochondrial genome as a partial regulator of nuclear function is providing new insights into the genetic mechanisms underlying age-related complex disease. Hum Genet. 2014;133:435–58.
Cagin U, Enriquez JA. The complex crosstalk between mitochondria and the nucleus: what goes in between? Int J Biochem Cell Biol. 2015;63:10–5.
Vivian CJ, Brinker AE, Graw S, Koestler DC, Legendre C, Gooden GC, et al. Mitochondrial genomic backgrounds affect nuclear DNA methylation and gene expression. Cancer Res. 2017;77:6202–14.
Latorre-Pellicer A, Moreno-Loshuertos R, Lechuga-Vieco AV, Sánchez-Cabo F, Torroja C, Acín-Pérez R, et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature. 2016;535:561–5.
Bellizzi D, D’Aquila P, Giordano M, Montesanto A, Passarino G. Global DNA methylation levels are modulated by mitochondrial DNA variants. Epigenomics. 2012;4:17–27.
Kelly RDW, Mahmud A, McKenzie M, Trounce IA, St John JC. Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma a. Nucleic Acids Res. 2012;40:10124–38.
Lee W, Johnson J, Gough DJ, Donoghue J, Cagnone GLM, Vaghjiani V, et al. Mitochondrial DNA copy number is regulated by DNA methylation and demethylation of POLGA in stem and cancer cells and their differentiated progeny. Cell Death Dis. 2015;6:e1664.
Smiraglia DJ, Kulawiec M, Bistulfi GL, Gupta SG, Singh KK. A novel role for mitochondria in regulating epigenetic modification in the nucleus. Cancer Biol Ther. 2008;7:1182–90.
Xie C, Naito A, Mizumachi T, Evans TT, Douglas MG, Cooney CA, et al. Mitochondrial regulation of cancer associated nuclear DNA methylation. Biochem Biophys Res Commun. 2007;364:656–61.
Guha M, Srinivasan S, Guja K, Mejia E, Garcia-Diaz M, Johnson FB, et al. HnRNPA2 is a novel histone acetyltransferase that mediates mitochondrial stress-induced nuclear gene expression. Cell Discov. 2016;2:16045.
Sun X, Johnson J, St. John JC. Global DNA methylation synergistically regulates the nuclear and mitochondrial genomes in glioblastoma cells. Nucleic Acids Res 2018;46:5977–5995.
Sun X, St John JC. 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. Epigenetics Chromatin. 2018 [cited 2020 May 13];11. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136172/.
The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am J Epidemiol. 1989;129:687–702.
MitoPipeline G. MitoPipeline. MitoPipeline. 2018 [cited 2019 Nov 27]. Available from: http://genvisis.org/MitoPipeline/.
Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012;28:882–3.
Chen Y, Lemire M, Choufani S, Butcher DT, Grafodatskaya D, Zanke BW, et al. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics. 2013;8:203–9.
Teschendorff AE, Marabita F, Lechner M, Bartlett T, Tegner J, Gomez-Cabrero D, et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics. 2013;29:189–96.
Pidsley R, Wong CC, Volta M, Lunnon K, Mill J, Schalkwyk LC. A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genomics. 2013;14:293.
Fortin J-P, Labbe A, Lemire M, Zanke BW, Hudson TJ, Fertig EJ, et al. Functional normalization of 450k methylation array data improves replication in large cancer studies. Genome Biol. 2014 [cited 2018 Dec 16];15. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283580/.
Houseman EA, Molitor J, Marsit CJ. Reference-free cell mixture adjustments in analysis of DNA methylation data. Bioinformatics. 2014;30:1431–9.
Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1.
Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA, et al. The cardiovascular health study: design and rationale. Ann Epidemiol. 1991;1:263–76.
Dawber TR, Meadors GF, Moore FE. Epidemiological approaches to heart disease: the Framingham study. Am J Public Health Nations Health. 1951;41:279–81.
Ding J, Sidore C, Butler TJ, Wing MK, Qian Y, Meirelles O, et al. Assessing mitochondrial DNA variation and copy number in lymphocytes of ~2,000 Sardinians using tailored sequencing analysis tools. PLoS Genet. 2015;11:e1005306.
Roby J, Just Allan C, Marioni Riccardo E, Pilling Luke C, Reynolds Lindsay M, Mandaviya Pooja R, et al. Epigenetic signatures of cigarette smoking. Circ Cardiovasc Genet. 2016;9:436–47.
Shabalin AA. Matrix eQTL: ultra fast eQTL analysis via large matrix operations. Bioinformatics. 2012;28:1353–8.
Han B, Eskin E. Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am J Hum Genet. 2011;88:586–98.
Brion M-JA, Shakhbazov K, Visscher PM. Calculating statistical power in Mendelian randomization studies. Int J Epidemiol. 2013;42:1497–501.
Castellani C, Sumpter J, Newcomb C, Arking D. HEK293 TFAM Knockout Methylation Study. Gene Expression Omnibus (GEO); 2019. Available from: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE133994.
Fortin J-P, Triche TJ, Hansen KD. Preprocessing, normalization and integration of the Illumina HumanMethylationEPIC array with minfi. Bioinformatics. 2017;33:558–60.
Castellani C, Sumpter J, Newcomb C, Arking D. HEK293 TFAM Knockout Expression Study. Gene Expression Omnibus (GEO); 2019. Available from: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE134048.
Bray NL, Pimentel H, Melsted P, Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016;34:525–7.
Pimentel H, Bray NL, Puente S, Melsted P, Pachter L. Differential analysis of RNA-seq incorporating quantification uncertainty. Nat Methods. 2017;14:687–90.
Huang H, Chanda P, Alonso A, Bader JS, Arking DE. Gene-based tests of association. PLoS Genet. 2011;7:e1002177.
Geeleher P, Hartnett L, Egan LJ, Golden A, Raja Ali RA, Seoighe C. Gene-set analysis is severely biased when applied to genome-wide methylation data. Bioinformatics. 2013;29:1851–7.
Young MD, Wakefield MJ, Smyth GK, Oshlack A. Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol. 2010;11:R14.
Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M, Hultenby K, et al. Mitochondrial transcription factor a regulates mtDNA copy number in mammals. Hum Mol Genet. 2004;13:935–44.
de Oliveira VC, Moreira GSA, Bressan FF, Gomes Mariano Junior C, KCS R, Charpentier M, et al. Edition of TFAM gene by CRISPR/Cas9 technology in bovine model. PLoS ONE. 2019;14:e0213376.
Kanki T, Ohgaki K, Gaspari M, Gustafsson CM, Fukuoh A, Sasaki N, et al. Architectural role of mitochondrial transcription factor A in maintenance of human mitochondrial DNA. Mol Cell Biol. 2004;24:9823–34.
Longchamps RJ, Castellani CA, Yang SY, Newcomb CE, Sumpter JA, Lane J, et al. Evaluation of mitochondrial DNA copy number estimation techniques. PLoS One. 2020;15:e0228166.
Roubicek DA, de Souza-Pinto NC. Mitochondria and mitochondrial DNA as relevant targets for environmental contaminants. Toxicology. 2017;391:100–8.
Munot K, Bell SM, Lane S, Horgan K, Hanby AM, Speirs V. Pattern of expression of genes linked to epigenetic silencing in human breast cancer. Hum Pathol. 2006;37:989–99.
Yu M, Zhou Y, Shi Y, Ning L, Yang Y, Wei X, et al. Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB Life. 2007;59:450–7.
Timinskas A, Au Z, Ku V. Atherosclerosis: alterations in cell communication; 2007. p. 6.
Bayraktar G, Yuanxiang P, Confettura AD, Gomes GM, Raza SA, Stork O, et al. Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus. Neuropsychopharmacology. Nature Publishing Group. 2020. p. 1–11.
Guantes R, Rastrojo A, Neves R, Lima A, Aguado B, Iborra FJ. Global variability in gene expression and alternative splicing is modulated by mitochondrial content. Genome Res. 2015;25:633–44.
Ulrey CL, Liu L, Andrews LG, Tollefsbol TO. The impact of metabolism on DNA methylation. Hum Mol Genet. Oxford Academic. 2005;14:R139–47.
Day JJ, Kennedy AJ, Sweatt JD. DNA methylation and its implications and accessibility for neuropsychiatric therapeutics. Annu Rev Pharmacol Toxicol. 2015;55:591–611.
Hu L, Li Z, Cheng J, Rao Q, Gong W, Liu M, et al. Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation. Cell. 2013;155:1545–55.