线粒体表观遗传学研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2017-0649

摘要/Abstract

摘要： 作为细胞内的“动力工厂”,线粒体是细胞内进行氧化磷酸化反应和形成ATP的主要场所。传统观点曾认为线粒体缺乏表观遗传机制,但线粒体DNA甲基化酶以及线粒体DNA中5-甲基胞嘧啶与5-羟甲基胞嘧啶的发现推翻了这一论断。在线粒体中,DNA甲基化酶、DNA甲基化模式及DNA羟甲基化模式与核基因组DNA相比均存在较大差异,而外界环境中不同因子的变化也会对线粒体DNA的甲基化状态造成影响。除此之外,线粒体DNA的表观遗传因素还包括线粒体长链非编码RNA、线粒体miRNA和线粒体DNA结合蛋白。随着研究技术手段的不断完善,将线粒体DNA的甲基化状态作为生物标记的应用将日益广泛,其与基因组表观遗传调控的关联也将得到进一步的揭示。

关键词: 线粒体DNA, 表观遗传学, 5-甲基胞嘧啶, 5-羟甲基胞嘧啶

Abstract: As the “power house” in the cell,mitochondrion is the main organelle to carry out the reaction of oxidative phosphorylation and to generate most of the ATP. Traditionally,it is suggested that mitochondria was lack of any epigenetic mechanism,but the discovery of DNA methyltransferase,5-methylcytosine,and 5-hydroxymethylcytosine in mammalian mitochondria in 2011 contradicted with this statement. In mitochondria,the DNA methyltransferase and the patterns of both DNA methylation and DNA hydroxymethylation are quite different compared with the nuclear genome DNA,and the changes of environmental factors would cause the impacts on the mitochondrial DNA methylation . In addition,epigenetic factors of mitochondrial DNA also include mitochondrial long noncoding RNA,mitochondrial miRNA and mitochondrial DNA binding protein. With the continuous improvement of research techniques,the use of mitochondrial DNA methylation as biomarker will become more extensive and its association with nuclear epigenetics will be further revealed.

Key words: mitochondrial DNA（mtDNA）, epigenetics, 5-methylcytosine, 5-hydroxymethylcytosine

柳莹, 高丽, 冯俊荣. 线粒体表观遗传学研究进展[J]. 生物技术通报, 2018, 34(1): 60-66.

LIU Ying, GAO Li, FENG Jun-rong. Research Progress on Mitochondrial Epigenetics[J]. Biotechnology Bulletin, 2018, 34(1): 60-66.

参考文献

[1] Arciuch AVG, Elguero ME, Poderoso JJ, et al. Mitochondrial regulation of cell cycle and proliferation[J]. Antioxidants & Redox Signaling, 2012, 16（10）：1150-1180.
[2] Cali T, Ottolini D, Brini M. Mitochondrial Ca 2+ as a key regulator of mitochondrial activities[J]. Advances in Mitochondrial Medicine, 2012, 942：53-73.
[3] Henze K, Martin W. Evolutionary biology：essence of mitochondria [J]. Nature, 2003, 426（6963）：127-128.
[4] Shock LS, Thakkar PV, Peterson EJ, et al. DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria[J]. Proc Natl Acad Sci USA, 2011, 108（9）：3630-3635.
[5] Manev H, Dzitoyeva S, Chen H. Mitochondrial DNA：a blind spot in neuroepigenetics[J]. Biomolecular Concepts, 2012, 3（2）：107 -115.
[6] Jurkowski TP, Meusburger M, Phalke S, et al. Human DNMT2 methylates tRNA（Asp）molecules using a DNA methyltransferase-like catalytic mechanism[J]. RNA, 2008, 14（8）：1663-1670.
[7] Chestnut BA, Chang Q, Price A, et al. Epigenetic regulation of motor neuron cell death through DNA methylation[J]. Journal of Neuroscience, 2011, 31（46）：16619-16636.
[8] Scafone T, Cristiani C, Crocco P, et al. Evidence of methylation within the control region of human mitochondrial DNA[M]. Rome：12th FISV Congress, 2012.
[9] Chen CC, Wang KY, Shen CK. The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases[J]. J Biol Chem, 2012, 287：33116-33121.
[10] Manev H, Dzitoyeva S. Progress in mitochondrial epigenetics[J]. Biomolecular Concepts, 2013;4（4）：381-389.
[11] Fan SC, Li CZ, Pei YF. DNA methylome data analysis in human genome[J]. Science China, 2015, 45（5）：450-459.
[12] Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome[J]. Nature, 2001, 409（6822）：860-921.
[13] Ghosh S, Sengupta S, Scaria V. Comparative analysis of human mitochondrial methylomes shows distinct patterns of epigenetic regulation in mitochondria. Molecular Cytogenetics, 2014, 18：58-62 .
[14] Bellizzi D, D’Aquila P, Scafone1 T, et al. The control region of mitochondrial DNA shows an unusual CpG and non-CpG methylation pattern[J]. DNA Research, 2013, 20（6）：537.
[15] Penn NW, Suwalski R, O’Riley C, et al. The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid[J]. Biochemical Journal, 1972, 126（4）：781-790.
[16] Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1[J]. Science 2009, 324：930-935.
[17] Wagner JR, Cadet J. Oxidation reactions of cytosine DNA components by hydroxyl radical and one-electron oxidants in aerated aqueous solutions[J]. Accounts of Chemical Research, 2010;43：56 -71.
[18] Sun Z, Jolyon T, Borgaro JG, et al. High-resolution enzymatic mapping of genomic 5-hydroxymethylcytosine in mouse embryonic stem cells[J]. Cell Reports, 2013;3（3）：567-576.
[19] Jia Y, Li R, Cong R, et al. Maternal low-protein diet affects epigenetic regulation of hepatic mitochondrial DNA transcription in a sex-specific manner in newborn piglets associated with GR binding to its promoter[J]. PLoS One. 2013, 8（5）：e63855.
[20] Liao K, Yan J, Mai K, et al. Dietary olive and perilla oils affect liver mitochondrial DNA methylation in large yellow croakers[J]. Journal of Nutrition, 2015, 145（11）：2479-2485.
[21] Byun HM, Panni T, Motta V, et al. Effects of airborne pollutants on mitochondrial DNA methylation[J]. Particle & Fibre Toxicology, 2013, 10（1）：18.
[22] Yang L, Xia B, Yang X, et al. Mitochondrial DNA hypomethylation in chrome plating workers[J]. Toxicology Letter, 2016, 243：1-6.
[23] Byun HM, Colicino E, Trevisi L, et al. Effects of Air Pollution and Blood Mitochondrial DNA Methylation on Markers of Heart Rate Variability[J]. Journal of the American Heart Association, 2016, 5（4）：e003218.
[24] Byun HM, Benachour N, Zalko D, et al. Epigenetic effects of low perinatal doses of flame retardant BDE-47 on mitochondrial and nuclear genes in rat offspring[J]. Toxicology, 2015, 328：152-159.
[25] Janssen BG, Gyselaers W, Byun HM, et al. Placental mitochondrial DNA and CYP1A1 gene methylation as molecular signatures for tobacco smoke exposure in pregnant women and the relevance for birth weight[J]. J Transl Med, 2017, 15（1）：5.
[26] Janssen BG, Byun HM, Gyselaers W, et al. Placental mitochondrial methylation and exposure to airborne particulate matter in the early life environment：an ENVIRONAGE birth cohort study[J]. Epigenetics. 2015, 10（6）：536-44.
[27] Mitalipov S, Wolf DP. Clinical and ethical implications of mitochondrial gene transfer[J]. Trends in Endocrinology & Metabolism. 2014, 25（1）：5-7.
[28] Baccarelli AA, Byun HM. Platelet mitochondrial DNA methylation：a potential new marker of cardiovascular disease[J]. Clinical Epigenetics, 2015, 7（1）：44.
[29] Blanch M, Mosquera JL, Ansoleaga B, et al. Altered mitochondrial DNA methylation pattern in Alzheimer disease-related pathology and in Parkinson disease[J]. American Journal of Pathology, 2016, 186（2）：385.
[30] Zheng LD, Linarelli LE, Liu L, et al. Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans[J]. Clinical Epigenetics. 2015, 7（1）：60.
[31] Mishra M, Kowluru RA. Epigenetic modification of mitochondrial DNA in the development of diabetic retinopathy[J]. Investigative Ophthalmology & Visual Science, 2015, 56（9）：5133.
[32] Pirola CJ, Gianotti TF, Burgueno AL, et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease[J]. Gut, 2013, 62（9）：1356-1363.
[33] Iacobazzi V, Castegna A, Infantino V, et al. Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool[J]. Molecular Genetics and Metabolism, 2013, 110（1-2）：25-34.
[34] Dzitoyeva S, Chen H, Manev H. Effect of aging on 5-hydroxymethyl-cytosine in brain mitochondria[J]. Neurobiology of Aging, 2012, 33（12）：2881-2891.
[35] Giordano M, Cristiani C, Crocco P, et al. Methylation of the human mitochondrial 12S rRNA gene is correlated with aging[M]. Rome：12th FISV Congress, 2012.
[36] Kobayashi H, Sakurai T, Imai M, et al. Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks[J]. PLoS Genetics, 2012, 8：e1002440.
[37] Barzideh J, Scott RJ, Aitken RJ. Analysis of the global methylation status of human spermatozoa and its association with the tendency of these cells to enter apoptosis[J]. Andrologia, 2013, 45（6）：424-429.
[38] Lee JT. Epigenetic regulation by long noncoding RNAs[J]. Science, 2012, 338（6113）：1435-1439.
[39] Rackham O, Shearwood AM, Mercer TR, et al. Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins[J]. RNA, 2011, 17（12）：2085-2093.
[40] Vidaurre S, Fitzpatrick C, Burzio VA, et al. Down-regulation of the antisense mitochondrial non-coding RNAs（ncRNAs）is a unique vulnerability of cancer cells and a potential target for cancer therapy[J]. J Biol Chem. 2014, 289（39）：27182-98 .
[41] Duarte FV, Palmeira CM, Rolo AP. The role of microRNAs in mitochondria：small players acting wide[J]. Genes, 2014, 5（4）：865-86.
[42] Smalheiser NR, Lugli G, Thimmapuram J, et al. Mitochondrial small RNAs that are up-regulated in hippocampus during olfactory discrimination training in mice[J]. Mitochondrion, 2011, 11（6）：994-995.
[43] Duarte FV, Amorim JA, Palmeira CM, et al. Regulation of mitochondrial function and its impact in metabolic stress[J]. Current Medicinal Chemistry, 2015, 22（20）：2468.
[44] Rebelo AP, Dillon LM, Moraes CT. Mitochondrial DNA transcription regulation and nucleoid organization[J]. Journal of Inherited Metabolic Disease, 2011, 34（4）：941-951.
[45] Verdin E, Ott M. 50 years of protein acetylation：from gene regulation to epigenetics, metabolism and beyond[J]. Nature Reviews Molecular Cell Biology, 2015, 16（4）：258-264.
[46] Mercer TR, Neph S, Dinger ME, et al. The human mitochondrial transcriptome[J]. Cell. 2011, 146（4）：645-58.
[47] Richly E, Leister D. NUMTs in sequenced eukaryotic genomes[J]. Molecular Biology & Evolution, 2004, 21（6）：1081.
[48] Schmitz J, Piskurek O, Zischler H. Forty million years of independent evolution：a mitochondrial gene and its corresponding nuclear pseudogene in primates[J]. Journal of Molecular Evolution, 2005, 61（1）：1-11.
[49] Lambertini L, Byun HM. Mitochondrial epigenetics and environmental exposure[J]. Current Environmental Health Reports, 2016, 3（3）：214-224.
[50] Mourier T, Hansen AJ, Willerslev E, et al. The Human Genome Project reveals a continuous transfer of large mitochondrial fragments to the nucleus[J]. Molecular Biology & Evolution, 2001, 18（9）：1833-1837.
[51] Smiraglia DJ, Kulawiec M, Bistulfi GL, et al. A novel role for mitochondria in regulating epigenetic modification in the nucleus[J]. Mitochondrion, 2008, 7（8）：1182-1190.
[52] Bellizzi D, D’Aquila P, Giordano M, et al. Global DNA methylation levels are modulated by mitochondrial DNA variants[J]. Epigenomics, 2012;4（1）：17-27.