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DNA methylation program during development

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Frontiers in Biology

Abstract

DNA methylation is a key epigenetic mark when occurring in the promoter and enhancer regions regulates the accessibility of the binding protein and gene transcription. DNA methylation is inheritable and can be de novosynthesized, erased and reinstated, making it arguably one of the most dynamic upstream regulators for gene expression and the most influential pacer for development. Recent progress has demonstrated that two forms of cytosine methylation and two pathways for demethylation constitute ample complexity for an instructional program for orchestrated gene expression and development. The forum of the current discussion and review are whether there is such a program, if so what the DNA methylation program entails, and what environment can change the DNA methylation program. The translational implication of the DNA methylation program is also proposed.

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References

  • Anway M D, Leathers C, Skinner M K (2006). Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology, 147(12): 5515–5523

    Article  PubMed  CAS  Google Scholar 

  • Bakulski K M, Rozek L S, Dolinoy D C, Paulson H L, Hu H (2012). Alzheimer’s disease and environmental exposure to lead: the epidemiologic evidence and potential role of epigenetics. Curr Alzheimer Res, 9(5): 563–573

    PubMed  CAS  Google Scholar 

  • Bhutani N, Burns D M, Blau H M (2011). DNA demethylation dynamics. Cell, 146(6): 866–872

    Article  PubMed  CAS  Google Scholar 

  • Bird A (2002). DNA methylation patterns and epigenetic memory. Genes Dev, 16(1): 6–21

    Article  PubMed  CAS  Google Scholar 

  • Bird A P (1986). CpG-rich islands and the function of DNA methylation. Nature, 321(6067): 209–213

    Article  PubMed  CAS  Google Scholar 

  • Brandeis M, Ariel M, Cedar H (1993). Dynamics of DNA methylation during development. Bioessays, 15(11): 709–713

    Article  PubMed  CAS  Google Scholar 

  • Brown D C, Grace E, Sumner A T, Edmunds A T, Ellis P M (1995). ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome. Hum Genet, 96(4): 411–416

    Article  PubMed  CAS  Google Scholar 

  • Brown K D, Robertson K D (2007). DNMT1 knockout delivers a strong blow to genome stability and cell viability. Nat Genet, 39(3): 289–290

    Article  PubMed  CAS  Google Scholar 

  • Busslinger M, Hurst J, Flavell R A (1983). DNA methylation and the regulation of globin gene expression. Cell, 34(1): 197–206

    Article  PubMed  CAS  Google Scholar 

  • Caldji C, Hellstrom I C, Zhang T Y, Diorio J, Meaney M J (2011). Environmental regulation of the neural epigenome. FEBS Lett, 2049–2058

  • Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky P M, Meaney M J (1998). Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci USA, 95(9): 5335–5340

    Article  PubMed  CAS  Google Scholar 

  • Callaghan B, Feldman D, Gruis K, Feldman E (2011). The association of exposure to lead, mercury, and selenium and the development of amyotrophic lateral sclerosis and the epigenetic implications. Neurodegener Dis, 8(1–2): 1–8

    Article  PubMed  CAS  Google Scholar 

  • Champagne F A, Curley J P (2009). Epigenetic mechanisms mediating the long-term effects of maternal care on development. Neurosci Biobehav Rev, 33(4): 593–600

    Article  PubMed  Google Scholar 

  • Chia N, Wang L, Lu X, Senut M C, Brenner C, Ruden D M (2011). Hypothesis: environmental regulation of 5-hydroxymethylcytosine by oxidative stress. Epigenetics, 6(7): 853–856

    Article  PubMed  Google Scholar 

  • Dawlaty MM, Ganz K, Powell B E, Hu Y C, Markoulaki S, Cheng AW, Gao Q, Kim J, Choi S W, Page D C, Jaenisch R (2011). Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell, 9(2): 166–175

    Article  PubMed  CAS  Google Scholar 

  • De Carvalho D D, You J S, Jones P A (2010). DNA methylation and cellular reprogramming. Trends Cell Biol, 20(10): 609–617

    Article  PubMed  Google Scholar 

  • Deaton A M, Bird A (2011). CpG islands and the regulation of transcription. Genes Dev, 25(10): 1010–1022

    Article  PubMed  CAS  Google Scholar 

  • del Mazo J, Prantera G, Torres M, Ferraro M (1994). DNA methylation changes during mouse spermatogenesis. Chromosome Res, 2(2): 147–152

    Article  PubMed  Google Scholar 

  • Dolinoy D C (2008). The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutr Rev, 66(Suppl 1): S7–S11

    Article  PubMed  Google Scholar 

  • Dolinoy D C, Huang D, Jirtle R L (2007). Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA, 104(32): 13056–13061

    Article  PubMed  CAS  Google Scholar 

  • Dolinoy D C, Weidman J R, Waterland R A, Jirtle R L (2006). Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect, 114(4): 567–572

    Article  PubMed  CAS  Google Scholar 

  • Duhl D M, Vrieling H, Miller K A, Wolff G L, Barsh G S (1994). Neomorphic agouti mutations in obese yellow mice. Nat Genet, 8(1): 59–65

    Article  PubMed  CAS  Google Scholar 

  • Gardiner-Garden M, Frommer M (1987). CpG islands in vertebrate genomes. J Mol Biol, 196(2): 261–282

    Article  PubMed  CAS  Google Scholar 

  • Gisselsson D, Shao C, Tuck-Muller C M, Sogorovic S, Pålsson E, Smeets D, Ehrlich M (2005). Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells. Chromosoma, 114(2): 118–126

    Article  PubMed  CAS  Google Scholar 

  • Goll M G, Bestor T H (2005). Eukaryotic cytosine methyltransferases. Annu Rev Biochem, 74(1): 481–514

    Article  PubMed  CAS  Google Scholar 

  • Govorko D, Bekdash R A, Zhang C, Sarkar D K (2012). Male germline transmits fetal alcohol adverse effect on hypothalamic proopiomelanocortin gene across generations. Biol Psychiatry, 72(5): 378–388

    Article  PubMed  CAS  Google Scholar 

  • Green ML, Singh A V, Zhang Y, Nemeth K A, Sulik K K, Knudsen T B (2007). Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome. Dev Dyn, 236(2): 613–631

    Article  PubMed  CAS  Google Scholar 

  • Guo J U, Su Y, Zhong C, Ming G L, Song H (2011). Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell, 145(3): 423–434

    Article  PubMed  CAS  Google Scholar 

  • Heijmans B T, Tobi E W, Stein A D, Putter H, Blauw G J, Susser E S, Slagboom P E, Lumey L H (2008). Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA, 105(44): 17046–17049

    Article  PubMed  CAS  Google Scholar 

  • Hermann A, Gowher H, Jeltsch A (2004). Biochemistry and biology of mammalian DNA methyltransferases. Cell Mol Life Sci, 61(19–20): 2571–2587

    Article  PubMed  CAS  Google Scholar 

  • Inoue A, Shen L, Dai Q, He C, Zhang Y (2011). Generation and replication-dependent dilution of 5fC and 5caC during mouse preimplantation development. Cell Res, 21(12): 1670–1676

    Article  PubMed  CAS  Google Scholar 

  • Inoue A, Zhang Y (2011). Replication-dependent loss of 5-hydroxymethylcytosine in mouse preimplantation embryos. Science, 334 (6053): 194

    Article  PubMed  CAS  Google Scholar 

  • Iqbal K, Jin S G, Pfeifer G P, Szabó P E (2011). Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine. Proc Natl Acad Sci USA, 108(9): 3642–3647

    Article  PubMed  CAS  Google Scholar 

  • Ito S, D’Alessio A C, Taranova O V, Hong K, Sowers L C, Zhang Y (2010). Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature, 466:1129–1136

    Article  PubMed  CAS  Google Scholar 

  • Ito S, Shen L, Dai Q, Wu S C, Collins L B, Swenberg J A, He C, Zhang Y (2011). Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science, 333(6047): 1300–1303

    Article  PubMed  CAS  Google Scholar 

  • Jeffy B D, Chirnomas R B, Romagnolo D F (2002). Epigenetics of breast cancer: polycyclic aromatic hydrocarbons as risk factors. Environ Mol Mutagen, 39(2–3): 235–244

    Article  PubMed  CAS  Google Scholar 

  • Jones P A, Takai D (2001). The role of DNA methylation in mammalian epigenetics. Science, 293(5532): 1068–1070

    Article  PubMed  CAS  Google Scholar 

  • Kaati G, Bygren L O, Edvinsson S (2002). Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet, 10(11): 682–688

    Article  PubMed  CAS  Google Scholar 

  • Kafri T, Gao X, Razin A (1993). Mechanistic aspects of genome-wide demethylation in the preimplantation mouse embryo. Proc Natl Acad Sci USA, 90(22): 10558–10562

    Article  PubMed  CAS  Google Scholar 

  • Kahn H S, Graff M, Stein A D, Lumey L H (2009). A fingerprint marker from early gestation associated with diabetes in middle age: the Dutch Hunger Winter Families Study. Int J Epidemiol, 38(1): 101–109

    Article  PubMed  Google Scholar 

  • Kaminen-Ahola N, Ahola A, Maga M, Mallitt K A, Fahey P, Cox T C, Whitelaw E, Chong S (2010). Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model. PLoS Genet, 6(1): e1000811

    Article  PubMed  Google Scholar 

  • Karymov M A, Tomschik M, Leuba S H, Caiafa P, Zlatanova J (2001). DNA methylation-dependent chromatin fiber compaction in vivo and in vitro: requirement for linker histone. FASEB J, 15(14): 2631–2641

    Article  PubMed  CAS  Google Scholar 

  • Kile M L, Baccarelli A, Hoffman E, Tarantini L, Quamruzzaman Q, Rahman M, Mahiuddin G, Mostofa G, Hsueh Y M, Wright R O, Christiani D C (2012). Prenatal arsenic exposure and DNA methylation in maternal and umbilical cord blood leukocytes. Environ Health Perspect, 120(7): 1061–1066

    Article  PubMed  CAS  Google Scholar 

  • Koh K P, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer C A, Mostoslavsky G, Lahesmaa R, Orkin S H, Rodig S J, Daley G Q, Rao A (2011). Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell, 8(2): 200–213

    Article  PubMed  CAS  Google Scholar 

  • Kriaucionis S, Heintz N (2009). The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science, 324(5929): 929–930

    Article  PubMed  CAS  Google Scholar 

  • Kucharski R, Maleszka J, Foret S, Maleszka R (2008). Nutritional control of reproductive status in honeybees via DNA methylation. Science, 319(5871): 1827–1830

    Article  PubMed  CAS  Google Scholar 

  • Kundakovic M, Champagne F A (2011). Epigenetic perspective on the developmental effects of bisphenol A. Brain Behav Immun, 25(6): 1084–1093

    Article  PubMed  CAS  Google Scholar 

  • Lister R, Pelizzola M, Dowen R H, Hawkins R D, Hon G, Tonti-Filippini J, Nery J R, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar A H, Thomson J A, Ren B, Ecker J R (2009). Human DNA methylomes at base resolution show widespread epigenomic differences. Nature, 462(7271): 315–322

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Balaraman Y, Wang G, Nephew K P, Zhou F C (2009). Alcohol exposure alters DNA methylation profiles in mouse embryos at early neurulation. Epigenetics, 4(7): 500–511

    Article  PubMed  CAS  Google Scholar 

  • Lumey L H, Stein A D (2009). Transgenerational effects of prenatal exposure to the Dutch famine. BJOG, 116(6): 868, author reply 868

    Article  PubMed  CAS  Google Scholar 

  • Lumey L H, Stein A D, Kahn H S, van der Pal-de Bruin KM, Blauw G J, Zybert P A, Susser E S (2007). Cohort profile: the Dutch Hunger Winter families study. Int J Epidemiol, 36(6): 1196–1204

    Article  PubMed  CAS  Google Scholar 

  • Martínez L, Jiménez V, García-Sepúlveda C, Ceballos F, Delgado J M, Niño-Moreno P, Doniz L, Saavedra-Alanís V, Castillo C G, Santoyo M E, González-Amaro R, Jiménez-Capdeville M E (2011). Impact of early developmental arsenic exposure on promotor CpG-island methylation of genes involved in neuronal plasticity. Neurochem Int, 58(5): 574–581

    Article  PubMed  Google Scholar 

  • Mason J B, Choi S W (2005). Effects of alcohol on folate metabolism: implications for carcinogenesis. Alcohol, 35(3): 235–241

    Article  PubMed  CAS  Google Scholar 

  • McKay J A, Williams E A, Mathers J C (2004). Folate and DNA methylation during in utero development and aging. Biochem Soc Trans, 32(Pt 6): 1006–1007

    PubMed  CAS  Google Scholar 

  • Meaney M J, Szyf M (2005). Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci, 7(2): 103–123

    PubMed  Google Scholar 

  • Morgan H D, Santos F, Green K, Dean W, Reik W (2005). Epigenetic reprogramming in mammals. Hum Mol Genet, 14(Spec No 1): R47–R58

    Article  PubMed  CAS  Google Scholar 

  • Nakanishi M O, Hayakawa K, Nakabayashi K, Hata K, Shiota K, Tanaka S (2012). Trophoblast-specific DNA methylation occurs after the segregation of the trophectoderm and inner cell mass in the mouse periimplantation embryo. Epigenetics, 7(2): 173–182

    Article  PubMed  CAS  Google Scholar 

  • Okano M, Li E (2002). Genetic analyses of DNA methyltransferase genes in mouse model system. J Nutr, 132(8 Suppl): 2462S–2465S

    PubMed  CAS  Google Scholar 

  • Otero N K, Thomas J D, Saski C A, Xia X, Kelly S J (2012). Choline supplementation and DNA methylation in the hippocampus and prefrontal cortex of rats exposed to alcohol during development. Alcohol Clin Exp Res, doi: 10.1111/j.1530-0277.2012.01784.x

  • Ouko L A, Shantikumar K, Knezovich J, Haycock P, Schnugh D J, Ramsay M (2009). Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IGDMR in male gametes-implications for fetal alcohol spectrum disorders. Alcohol Clin Exp Res, 33(9):1615–1627

    Article  PubMed  CAS  Google Scholar 

  • Perera F, Herbstman J (2011). Prenatal environmental exposures, epigenetics, and disease. Reprod Toxicol, 31(3): 363–373

    Article  PubMed  CAS  Google Scholar 

  • Pilsner J R, Hu H, Ettinger A, Sánchez B N, Wright R O, Cantonwine D, Lazarus A, Lamadrid-Figueroa H, Mercado-García A, Téllez-RojoM M, Hernández-Avila M (2009). Influence of prenatal lead exposure on genomic methylation of cord blood DNA. Environ Health Perspect, 117(9): 1466–1471

    PubMed  CAS  Google Scholar 

  • Ramsahoye B H, Davies C S, Mills K I (1996). DNA methylation: biology and significance. Blood Rev, 10(4): 249–261

    Article  PubMed  CAS  Google Scholar 

  • Schermelleh L, Haemmer A, Spada F, Rösing N, Meilinger D, Rothbauer U, Cardoso M C, Leonhardt H (2007). Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylation. Nucleic Acids Res, 35(13): 4301–4312

    Article  PubMed  CAS  Google Scholar 

  • Schmid M, Haaf T, Grunert D (1984). 5-Azacytidine-induced undercondensations in human chromosomes. Hum Genet, 67(3): 257–263

    Article  PubMed  CAS  Google Scholar 

  • Singh R P, Shiue K, Schomberg D, Zhou F C (2009). Cellular epigenetic modifications of neural stem cell differentiation. Cell Transplant, 18 (10): 1197–1211

    Article  PubMed  Google Scholar 

  • Stein A D, Zybert P A, van de Bor M, Lumey L H (2004). Intrauterine famine exposure and body proportions at birth: the Dutch Hunger Winter. Int J Epidemiol, 33(4): 831–836

    Article  PubMed  Google Scholar 

  • Stein A D, Zybert P A, van der Pal-de Bruin K, Lumey L H (2006). Exposure to famine during gestation, size at birth, and blood pressure at age 59 y: evidence from the Dutch Famine. Eur J Epidemiol, 21 (10): 759–765

    Article  PubMed  Google Scholar 

  • Suter M, Ma J, Harris A, Patterson L, Brown K A, Shope C, Showalter L, Abramovici A, Aagaard-Tillery K M (2011). Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression. Epigenetics, 6(11): 1284–1294

    Article  PubMed  CAS  Google Scholar 

  • Szulwach K E, Li X, Li Y, Song C X, Wu H, Dai Q, Irier H, Upadhyay A K, Gearing M, Levey A I, Vasanthakumar A, Godley L A, Chang Q, Cheng X, He C, Jin P (2011). 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci, 14:1607–1616

    Article  PubMed  CAS  Google Scholar 

  • Tahiliani M, Koh K P, Shen Y, Pastor W A, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu D R, Aravind L, Rao A (2009). Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science, 324(5929): 930–935

    Article  PubMed  CAS  Google Scholar 

  • Tang W Y, Levin L, Talaska G, Cheung Y Y, Herbstman J, Tang D, Miller R L, Perera F, Ho S M (2012). Maternal Exposure to Polycyclic Aromatic Hydrocarbons and 5′-CpG Methylation of Interferon-Γ in Cord White Blood Cells. Environ Health Perspect, 120(8): 1195–1200

    Article  PubMed  CAS  Google Scholar 

  • Tawa R, Ono T, Kurishita A, Okada S, Hirose S (1990). Changes of DNA methylation level during pre- and postnatal periods in mice. Differentiation, 45(1): 44–48

    Article  PubMed  CAS  Google Scholar 

  • Waterland R A, Jirtle R L (2003). Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol, 23(15): 5293–5300

    Article  PubMed  CAS  Google Scholar 

  • Wolffe A P, Jones P L, Wade P A (1999). DNA demethylation. Proc Natl Acad Sci USA, 96(11): 5894–5896

    Article  PubMed  CAS  Google Scholar 

  • Wright R J (2011). Epidemiology of stress and asthma: from constricting communities and fragile families to epigenetics. Immunol Allergy Clin North Am, 31(1): 19–39

    Article  PubMed  Google Scholar 

  • Wu H, D’Alessio A C, Ito S, Wang Z, Cui K, Zhao K, Sun Y E, Zhang Y (2011). Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev, 25(7): 679–684

    Article  PubMed  CAS  Google Scholar 

  • Wu Q, Ohsako S, Ishimura R, Suzuki J S, Tohyama C (2004). Exposure of mouse preimplantation embryos to 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2. Biol Reprod, 70(6): 1790–1797

    Article  PubMed  CAS  Google Scholar 

  • Wu S C, Zhang Y (2010). Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol, 11(9): 607–620

    Article  PubMed  CAS  Google Scholar 

  • Xu X F, Cheng F, Du L Z (2011). Epigenetic regulation of pulmonary arterial hypertension. Hypertens Res, 34(9): 981–986

    Article  PubMed  CAS  Google Scholar 

  • Yildirim O, Li R, Hung J H, Chen P B, Dong X, Ee L S, Weng Z, Rando O J, Fazzio T G (2011). Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell, 147(7): 1498–1510

    Article  PubMed  CAS  Google Scholar 

  • Yisraeli J, Frank D, Razin A, Cedar H (1988). Effect of in vitro DNA methylation on beta-globin gene expression. Proc Natl Acad Sci USA, 85(13): 4638–4642

    Article  PubMed  CAS  Google Scholar 

  • Zeisel S H (2007). Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline. IUBMB Life, 59(6): 380–387

    Article  PubMed  CAS  Google Scholar 

  • Zhou F C, Balaraman Y, Teng M, Liu Y, Singh R P, Nephew K P (2011a). Alcohol alters DNA methylation patterns and inhibits neural stem cell differentiation. Alcohol Clin Exp Res, 35(4): 735–746

    Article  PubMed  CAS  Google Scholar 

  • Zhou F C, Chen Y, Love A (2011b). Cellular DNA methylation program during neurulation and its alteration by alcohol exposure. Birth Defects Res A Clin Mol Teratol, 91(8): 703–715

    Article  PubMed  CAS  Google Scholar 

  • Zhou F C, Zhao Q, Liu Y, Goodlett C R, Liang T, McClintick J N, Edenberg H J, Li L (2011c). Alteration of gene expression by alcohol exposure at early neurulation. BMC Genomics, 12(1): 124

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Anatomy and Cell Biology, Stark Neuroscience Research Institute, Indiana University School Medicine, Indianapolis, IN, 46202, USA

    Feng C. Zhou

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Zhou, F.C. DNA methylation program during development. Front. Biol. 7, 485–494 (2012). https://doi.org/10.1007/s11515-012-9246-1

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