Plasticity of DNA methylation in mouse T cell activation and differentiation

BMC Molecular Biology

Jun Y Fan⁴  M Frances Shannon¹  Chao Sun³  Stephen J Ohms²  Lina Ma⁴  Guobing Chen⁴  Yan Li⁴ 

[1] The University of Canberra, Canberra ACT 2602, Australia;ACRF Biomolecular Resource Facility, John Curtin School of Medical Research, The Australian National University, Canberra ACT 2601, Australia;College of Animal Science & Technology, Northwest A&F University, Yangling Shaanxi 712100, P. R. China;Department of Genome Biology, John Curtin School of Medical Research, The Australian National University, Canberra ACT 2601, Australia

关键词: Il2, Csf2;    T cell differentiation;    T cell activation;    DNA demethylation;   

Others  :  1091980
DOI  :  10.1186/1471-2199-13-16

 received in 2011-12-20, accepted in 2012-05-29,  发布年份 2012

【 摘 要 】

Background

Circulating CD4⁺ T helper cells are activated through interactions with antigen presenting cells and undergo differentiation into specific T helper cell subsets depending on the type of antigen encountered. In addition, the relative composition of the circulating CD4⁺ T cell population changes as animals mature with an increased percentage of the population being memory/effector type cells.

Results

Here, we report on the highly plastic nature of DNA methylation at the genome-wide level as T cells undergo activation, differentiation and aging. Of particular note were the findings that DNA demethylation occurred rapidly following T cell activation and that all differentiated T cell populations displayed lower levels of global methylation than the non-differentiated population. In addition, T cells from older mice had a reduced level of DNA methylation, most likely explained by the increase in the memory/effector cell fraction. Although significant genome-wide changes were observed, changes in DNA methylation at individual genes were restricted to specific cell types. Changes in the expression of enzymes involved in DNA methylation and demethylation reflect in most cases the changes observed in the genome-wide DNA methylation status.

Conclusion

We have demonstrated that DNA methylation is dynamic and flexible in CD4+ T cells and changes rapidly both in a genome-wide and in a targeted manner during T cell activation, differentiation. These changes are accompanied by parallel changes in the enzymatic complexes that have been implicated in DNA methylation and demethylation implying that the balance between these opposing activities may play a role in the maintaining the methylation profile of a given cell type but also allow flexibility in a cell population that needs to respond rapidly to environmental signals.

【 授权许可】

   
2012 Li et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Holliday R: The inheritance of epigenetic defects. Science 1987, 238:163-170.
• [2]Morgan HD, Santos F, Green K, Dean W, Reik W: Epigenetic reprogramming in mammals. Hum Mol Genet 2005, 14:R47-R58.
• [3]Feng S, Jacobsen SE, Reik W: Epigenetic Reprogramming in Plant and Animal Development. Science 2010, 330:622-627.
• [4]Reik W, Dean W, Walter J: Epigenetic reprogramming in mammalian development. Science 2001, 293:1089-1093.
• [5]Calvanese V, Fernández AF, Urdinguio RG, Suárez-Alvarez B, Mangas C, Pérez-García V, Bueno C, Montes R, Ramos-Mejía V, Martínez-Camblor P, et al.: A promoter DNA demethylation landscape of human hematopoietic differentiation. Nucleic Acids Res 2012, 40:116-131.
• [6]Deaton AM, Webb S, Kerr ARW, Illingworth RS, Guy J, Andrews R, Bird A: Cell type-specific DNA methylation at intragenic CpG islands in the immune system. Genome Res 2011, 21:1074-1086.
• [7]Nishino K, Toyoda M, Yamazaki-Inoue M, Fukawatase Y, Chikazawa E, Sakaguchi H, Akutsu H, Umezawa A: DNA Methylation Dynamics in Human Induced Pluripotent Stem Cells over Time. PLoS Genet 2011, 7:e1002085.
• [8]Bocker MT, Hellwig I, Breiling A, Eckstein V, Ho AD, Lyko F: Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging. Blood 2011, 117:e182-e189.
• [9]Schmidl C, Klug M, Boeld TJ, Andreesen R, Hoffmann P, Edinger M, Rehli M: Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 2009, 19:1165-1174.
• [10]Shearstone JR, Pop R, Bock C, Boyle P, Meissner A, Socolovsky M: Global DNA demethylation during mouse erythropoiesis in vivo. Science 2011, 334:799-802.
• [11]Wu SC, Zhang Y: Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol 2010, 11:607-620.
• [12]Zhu J-K: Active DNA Demethylation Mediated by DNA Glycosylases. Annu Rev Genet 2009, 43:143-166.
• [13]Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A, Le Coz M, Devarajan K, Wessels A, Soprano D, et al.: Thymine DNA Glycosylase Is Essential for Active DNA Demethylation by Linked Deamination-Base Excision Repair. Cell 2011, 146:67-79.
• [14]Bhutani N, Burns DM, Blau HM: DNA Demethylation Dynamics. Cell 2011, 146:866-872.
• [15]Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, Zhang X, Bernstein BE, Nusbaum C, Jaffe DB, et al.: Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 2008, 454:5.
• [16]Ji H, Ehrlich LIR, Seita J, Murakami P, Doi A, Lindau P, Lee H, Aryee MJ, Irizarry RA, Kim K, et al.: Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 2010, 467:338-342.
• [17]Grubeck-Loebenstein B, Wick G: The aging of the immune system. Adv Immunol 2002, 80:243-284.
• [18]Kovaiou RD, Grubeck-Loebenstein B: Age-associated changes within CD4+ T cells. Immunol Lett 2006, 107:8-14.
• [19]Agarwal S, Rao A: Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 1998, 9:765-775.
• [20]Bix M, Locksley RM: Independent and Epigenetic Regulation of the Interleukin-4 Alleles in CD4+ T Cells. Science 1998, 281:1352-1354.
• [21]Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, Reid SP, Levy DE, Bromberg JS: Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 2009, 182:259-273.
• [22]Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, et al.: Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007, 5:e38.
• [23]Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J, Thiel A, Boeld TJ, Hoffmann P, Edinger M, et al.: DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 2007, 37:2378-2389.
• [24]Nagar M, Vernitsky H, Cohen Y, Dominissini D, Berkun Y, Rechavi G, Amariglio N, Goldstein I: Epigenetic inheritance of DNA methylation limits activation-induced expression of FOXP3 in conventional human CD25-CD4+ T cells. Int Immunol 2008, 20:1041-1055.
• [25]Kim H-P, Leonard WJ: CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 2007, 204:1543-1551.
• [26]Guan H, Nagarkatti PS, Nagarkatti M: CD44 Reciprocally Regulates the Differentiation of Encephalitogenic Th1/Th17 and Th2/Regulatory T Cells through Epigenetic Modulation Involving DNA Methylation of Cytokine Gene Promoters, Thereby Controlling the Development of Experimental Autoimmune Encephalomyelitis. J Immunol 2011, 186:6955-6964.
• [27]Chen X, Wang J, Woltring D, Gerondakis S, Shannon MF: Histone dynamics on the interleukin-2 gene in response to T-cell activation. Mol Cell Biol 2005, 25:3209-3219.
• [28]Bruniquel D, Schwartz RH: Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol 2003, 4:235-240.
• [29]Murayama A, Sakura K, Nakama M, Yasuzawa-Tanaka K, Fujita E, Tateishi Y, Wang Y, Ushijima T, Baba T, Shibuya K, et al.: A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. EMBO J 2006, 25:1081-1092.
• [30]Oakes CC, Smiraglia DJ, Plass C, Trasler JM, Robaire B: Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats. Proc Natl Acad Sci USA 2003, 100:1775-1780.
• [31]Calvanese V, Lara E, Kahn A, Fraga MF: The role of epigenetics in aging and age-related diseases. Ageing Res Rev 2009, 8:268-276.
• [32]So K, Tamura G, Honda T, Homma N, Waki T, Togawa N, Nishizuka S, Motoyama T: Multiple tumor suppressor genes are increasingly methylated with age in non-neoplastic gastric epithelia. Cancer Sci 2006, 97:1155-1158.
• [33]Jintaridth P, Mutirangura A: Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences. Physiol Genomics 2010, 41:194-200.
• [34]Whisler RL, Beiqing L, Chen M: Age-Related Decreases in IL-2 Production by Human T Cells Are Associated with Impaired Activation of Nuclear Transcriptional Factors AP-1 and NF-AT. Cell Immunol 1996, 169:185-195.
• [35]Haynes L, Linton P-J, Eaton SM, Tonkonogy SL, Swain SL: Interleukin 2, but Not Other Common γ Chain-Binding Cytokines, Can Reverse the Defect in Generation of Cd4 Effector T Cells from Naive T Cells of Aged Mice. J Exp Med 1999, 190:1013-1024.
• [36]Zhang Z, Deng C, Lu Q, Richardson B: Age-dependent DNA methylation changes in the ITGAL (CD11a) promoter. Mech Ageing Dev 2002, 123:1257-1268.
• [37]Kersh EN, Fitzpatrick DR, Murali-Krishna K, Shires J, Speck SH, Boss JM, Ahmed R: Rapid Demethylation of the IFN-gamma Gene Occurs in Memory but Not Naive CD8 T Cells. J Immunol 2006, 176:4083-4093.
• [38]Northrop JK, Thomas RM, Wells AD, Shen H: Epigenetic Remodeling of the IL-2 and IFN-gamma Loci in Memory CD8 T Cells Is Influenced by CD4 T Cells. J Immunol 2006, 177:1062-1069.
• [39]Jones PA, Liang G: Rethinking how DNA methylation patterns are maintained. Nat Rev Genet 2009, 10:805-811.
• [40]Robert M-F, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A, MacLeod AR: DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet 2003, 33:61-65.
• [41]Bird A: DNA methylation patterns and epigenetic memory. Genes Dev 2002, 16:6-21.
• [42]Morgan HD, Dean W, Coker HA, Reik W, Petersen-Mahrt SK: Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem 2004, 279:52353-52360.
• [43]Rai K, Huggins IJ, James SR, Karpf AR, Jones DA, Cairns BR: DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 2008, 135:1201-1212.
• [44]Hendrich B, Hardeland U, Ng HH, Jiricny J, Bird A: The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature 1999, 401:301-304.
• [45]Ma DK, Jang M-H, Guo JU, Kitabatake Y, M-l Chang, Pow-anpongkul N, Flavell RA, Lu B, G-l Ming, Song H: Neuronal Activity-Induced Gadd45b Promotes Epigenetic DNA Demethylation and Adult Neurogenesis. Science 2009, 323:1074-1077.
• [46]Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y: Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010, 466:1129-1133.
• [47]Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, et al.: Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1. Science 2009, 324:930-935.
• [48]Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y: Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine. Science 2011, 333:1300-1303.
• [49]He Y-F, Li B-Z, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, et al.: Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA. Science 2011, 333:1303-1307.
• [50]Saule P, Trauet J, Dutriez V, Lekeux V, Dessaint J-P, Labalette M: Accumulation of memory T cells from childhood to old age: Central and effector memory cells in CD4+ versus effector memory and terminally differentiated memory cells in CD8+ compartment. Mech Ageing Dev 2006, 127:274-281.
• [51]Utsuyama M, Hirokawa K, Kurashima C, Fukayama M, Inamatsu T, Suzuki K, Hashimoto W, Sato K: Differential age-change in the numbers of CD4 + CD45RA + and CD4 + CD29+ T-cell subsets in human peripheral-blood. Mech Ageing Dev 1992, 63:57-68.
• [52]Rao S, Gerondakis S, Woltring D, Shannon MF: c-Rel Is Required for Chromatin Remodeling Across the IL-2 Gene Promoter. J Immunol 2003, 170:3724-3731.
• [53]Holloway AF, Rao S, Chen X, Shannon MF: Changes in chromatin accessibility across the GM-CSF promoter upon T cell activation are dependent on nuclear factor kappaB proteins. J Exp Med 2003, 197:413-423.
• [54]Mohn F, Weber M, Schubeler D, Roloff TC: Methylated DNA immunoprecipitation (MeDIP). Methods Mol Biol 2009, 507:55-64.
• [55]Vucic EA, Wilson IM, Campbell JM, Lam WL: Methylation Analysis by DNA Immunoprecipitation (MeDIP). In Microarray Analysis of the Physical Genome: Methods and Protocols Edited by Pollack JR. 2009, 556:141-153.
• [56]Rao S, Procko E, Shannon MF: Chromatin Remodeling, Measured by a Novel Real-Time Polymerase Chain Reaction Assay, Across the Proximal Promoter Region of the IL-2 Gene. J Immunol 2001, 167:4494-4503.
• [57]Attema JL, Reeves R, Murray V, Levichkin I, Temple MD, Tremethick DJ, Shannon MF: The human IL-2 gene promoter can assemble a positioned nucleosome that becomes remodeled upon T cell activation. J Immunol 2002, 169:2466-2476.
• [58]Attema JL, Reeves R, Murray V, Levichkin I, Temple MD, Tremethick DJ, Shannon MF: The Human IL-2 Gene Promoter Can Assemble a Positioned Nucleosome That Becomes Remodeled Upon T Cell Activation. J Immunol 2002, 169:2466-2476.
• [59]Santangelo S, Cousins DJ, Triantaphyllopoulos K, Staynov DZ: Chromatin structure and DNA methylation of the IL-4 gene in human T(H)2 cells. Chromosome Res 2009, 17:485-496.
• [60]Makar KW, Perez-Melgosa M, Shnyreva M, Weaver WM, Fitzpatrick DR, Wilson CB: Active recruitment of DNA methyltransferases regulates interleukin 4 in thymocytes and T cells. Nat Immunol 2003, 4:1183-1190.
• [61]Winders BR, Schwartz RH, Bruniquel D: A Distinct Region of the Murine IFN-γ Promoter Is Hypomethylated from Early T Cell Development through Mature Naive and Th1 Cell Differentiation, but Is Hypermethylated in Th2 Cells. J Immunol 2004, 173:7377-7384.
• [62]Yano S, Ghosh P, Kusaba H, Buchholz M, Longo DL: Effect of promoter methylation on the regulation of IFN-gamma gene during in vitro differentiation of human peripheral blood T cells into a Th2 population. J Immunol 2003, 171:2510-2516.
• [63]Reik W: Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 2007, 447:425-432.
• [64]Hernandez DG, Nalls MA, Gibbs JR, Arepalli S, van der Brug M, Chong S, Moore M, Longo DL, Cookson MR, Traynor BJ, et al.: Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet 2011, 20:1164-1172.
• [65]Zhang F, Pomerantz JH, Sen G, Palermo AT, Blau HM: Active tissue-specific DNA demethylation conferred by somatic cell nuclei in stable heterokaryons. Proc Natl Acad Sci 2007, 104:4395-4400.
• [66]Oswald J, Engemann S, Lane N, Mayer W, Olek A, Fundele R, Dean W, Reik W, Walter J: Active demethylation of the paternal genome in the mouse zygote. Curr Biol 2000, 10:475-478.
• [67]Nakamura T, Arai Y, Umehara H, Masuhara M, Kimura T, Taniguchi H, Sekimoto T, Ikawa M, Yoneda Y, Okabe M, et al.: PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat Cell Biol 2007, 9:64-71.
• [68]Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE: DNA Methylation-Related Chromatin Remodeling in Activity-Dependent Bdnf Gene Regulation. Science 2003, 302:890-893.
• [69]Lee YK, Mukasa R, Hatton RD, Weaver CT: Developmental plasticity of Th17 and Treg cells. Curr Opin Immunol 2009, 21:274-280.
• [70]Lal G, Bromberg JS: Epigenetic mechanisms of regulation of Foxp3 expression. Blood 2009, 114:3727-3735.
• [71]Li Y, Zhao M, Yin H, Gao F, Wu X, Luo Y, Zhao S, Zhang X, Su Y, Hu N, et al.: Overexpression of the growth arrest and DNA damage-induced 45α gene contributes to autoimmunity by promoting DNA demethylation in lupus T cells. Arthritis Rheum 2010, 62:1438-1447.
• [72]Yang J, Zhu H, Murphy TL, Ouyang W, Murphy KM: IL-18-stimulated GADD45[beta] required in cytokine-induced, but not TCR-induced, IFN-gamma production. Nat Immunol 2001, 2:157-164.
• [73]Lu B, Yu H, Chow C-w, Li B, Zheng W-p, Davis RJ, Flavell RA: GADD45³ Mediates the Activation of the p38 and JNK MAP Kinase Pathways and Cytokine Production in Effector TH1 Cells. Immunity 2001, 14:583-590.
• [74]Lu B, Ferrandino AF, Flavell RA: Gadd45[beta] is important for perpetuating cognate and inflammatory signals in T cells. Nat Immunol 2004, 5:38-44.
• [75]Yang Z, Song L, Huang C: Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades. Curr Cancer Drug Targets 2009, 9:915-930.
• [76]Balada E, Ordi-Ros J, Serrano-Acedo S, Martinez-Lostao L, Rosa-Leyva M, Vilardell-Tarrés M: Transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in CD4+ T cells from patients with systemic lupus erythematosus. Immunology 2008, 124:339-347.
• [77]Balada E, Ordi-Ros J, Serrano-Acedo S, Martinez-Lostao L, Vilardell-Tarres M: Transcript overexpression of the MBD2 and MBD4 genes in CD4+ T cells from systemic lupus erythematosus patients. J Leukoc Biol 2007, 81:1609-1616.
• [78]Quddus J, Johnson KJ, Gavalchin J, Amento EP, Chrisp CE, Yung RL, Richardson BC: Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J Clin Invest 1993, 92:38-53.
• [79]Kaplan MJ, Lu Q, Wu A, Attwood J, Richardson B: Demethylation of Promoter Regulatory Elements Contributes to Perforin Overexpression in CD4+ Lupus T Cells. J Immunol 2004, 172:3652-3661.
• [80]Bending D: Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest 2009, 119:565-572.
• [81]Streeck H, Cohen KW, Jolin JS, Brockman MA, Meier A, Power KA, Waring MT, Alter G, Altfeld M: Rapid ex vivo isolation and long-term culture of human Th17 cells. J Immunol Methods 2008, 333:115-125.