Review Topical Sections

The epigenetic landscape of innate immunity

  • Received: 22 December 2016 Accepted: 13 March 2017 Published: 23 March 2017
  • The inflammatory response is the first line of defense against infectious agents or tissue damage. Innate immune cells are the crucial effectors regulating the different phase of inflammation. Their ability to timely develop an immune response is tightly controlled by the interplay of transcriptional and epigenetic mechanisms. The immunological imprinting elicited by exposure to different concentrations and types of infectious agents determine the functional fate of immune cells, forming the basis of innate immune memory. In this review we highlight the best-characterized examples of gene reprogramming occurring during different phases of inflammation with particular emphasis on the epigenetic marks that determine the specificity of the immune response. We further review the potential of cutting edge experimental techniques that have recently helped to reveal the deep complexity of epigenetic regulation during the inflammatory response.

    Citation: Mariacristina De Luca, Kevin Pels, Susana Moleirinho, Graziella Curtale. The epigenetic landscape of innate immunity[J]. AIMS Molecular Science, 2017, 4(1): 110-139. doi: 10.3934/molsci.2017.1.110

    Related Papers:

  • The inflammatory response is the first line of defense against infectious agents or tissue damage. Innate immune cells are the crucial effectors regulating the different phase of inflammation. Their ability to timely develop an immune response is tightly controlled by the interplay of transcriptional and epigenetic mechanisms. The immunological imprinting elicited by exposure to different concentrations and types of infectious agents determine the functional fate of immune cells, forming the basis of innate immune memory. In this review we highlight the best-characterized examples of gene reprogramming occurring during different phases of inflammation with particular emphasis on the epigenetic marks that determine the specificity of the immune response. We further review the potential of cutting edge experimental techniques that have recently helped to reveal the deep complexity of epigenetic regulation during the inflammatory response.
    [1] Kimbrell DA, Beutler B (2001) The evolution and genetics of innate immunity. Nat Rev Genet 2: 256-267. doi: 10.1038/35066006
    [2] Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140: 805-820. doi: 10.1016/j.cell.2010.01.022
    [3] Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11: 373-384. doi: 10.1038/ni.1863
    [4] O'Neill LA, Golenbock D, Bowie AG (2013) The history of Toll-like receptors - redefining innate immunity. Nat Rev Immunol 13: 453-460. doi: 10.1038/nri3446
    [5] Clarke TB (2014) Microbial programming of systemic innate immunity and resistance to infection. PLoS Pathog 10: e1004506. doi: 10.1371/journal.ppat.1004506
    [6] Drevets DA, Schawang JE, Dillon MJ, et al. (2008) Innate responses to systemic infection by intracellular bacteria trigger recruitment of Ly-6Chigh monocytes to the brain. J Immunol 181: 529-536. doi: 10.4049/jimmunol.181.1.529
    [7] Blach-Olszewska Z, Leszek J (2007) Mechanisms of over-activated innate immune system regulation in autoimmune and neurodegenerative disorders. Neuropsychiatr Dis Treat 3: 365-372.
    [8] Bachmann MF, Kopf M (2001) On the role of the innate immunity in autoimmune disease. J Exp Med 193: F47-50. doi: 10.1084/jem.193.12.F47
    [9] Alvarez-Errico D, Vento-Tormo R, Sieweke M, et al. (2015) Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol 15: 7-17.
    [10] Waddington CH (2012) The epigenotype. 1942. Int J Epidemiol 41: 10-13.
    [11] Saeed S, Quintin J, Kerstens HH, et al. (2014) Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345: 1251086. doi: 10.1126/science.1251086
    [12] Novakovic B, Habibi E, Wang SY, et al. (2016) beta-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance. Cell 167: 1354-1368. doi: 10.1016/j.cell.2016.09.034
    [13] NE II, Heward JA, Roux B, et al. (2014) Long non-coding RNAs and enhancer RNAs regulate the lipopolysaccharide-induced inflammatory response in human monocytes. Nat Commun 5: 3979.
    [14] Logie C, Stunnenberg HG (2016) Epigenetic memory: A macrophage perspective. Semin Immunol 28: 359-367. doi: 10.1016/j.smim.2016.06.003
    [15] O'Sullivan TE, Sun JC, Lanier LL (2015) Natural Killer Cell Memory. Immunity 43: 634-645. doi: 10.1016/j.immuni.2015.09.013
    [16] Netea MG, Quintin J, van der Meer JW (2011) Trained immunity: a memory for innate host defense. Cell Host Microbe 9: 355-361. doi: 10.1016/j.chom.2011.04.006
    [17] Quintin J, Cheng SC, van der Meer JW, et al. (2014) Innate immune memory: towards a better understanding of host defense mechanisms. Curr Opin Immunol 29: 1-7. doi: 10.1016/j.coi.2014.02.006
    [18] Netea MG, Joosten LA, Latz E, et al. (2016) Trained immunity: A program of innate immune memory in health and disease. Science 352: aaf1098. doi: 10.1126/science.aaf1098
    [19] Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9: 465-476.
    [20] Greer EL, Shi Y (2012) Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 13: 343-357.
    [21] Fang TC, Schaefer U, Mecklenbrauker I, et al. (2012) Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response. J Exp Med 209: 661-669. doi: 10.1084/jem.20112343
    [22] Martinez P, Denys A, Delos M, et al. (2015) Macrophage polarization alters the expression and sulfation pattern of glycosaminoglycans. Glycobiology 25: 502-513. doi: 10.1093/glycob/cwu137
    [23] Loke P, Nair MG, Parkinson J, et al. (2002) IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol 3: 7. doi: 10.1186/1471-2172-3-7
    [24] Jenkins SJ, Ruckerl D, Thomas GD, et al. (2013) IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1. J Exp Med 210: 2477-2491. doi: 10.1084/jem.20121999
    [25] Cabanel M, Brand C, Oliveira-Nunes MC, et al. (2015) Epigenetic Control of Macrophage Shape Transition towards an Atypical Elongated Phenotype by Histone Deacetylase Activity. PLoS One 10: e0132984. doi: 10.1371/journal.pone.0132984
    [26] Yang X, Wang X, Liu D, et al. (2014) Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b. Mol Endocrinol 28: 565-574. doi: 10.1210/me.2013-1293
    [27] Ramirez-Carrozzi VR, Nazarian AA, Li CC, et al. (2006) Selective and antagonistic functions of SWI/SNF and Mi-2beta nucleosome remodeling complexes during an inflammatory response. Genes Dev 20: 282-296. doi: 10.1101/gad.1383206
    [28] Ramirez-Carrozzi VR, Braas D, Bhatt DM, et al. (2009) A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138: 114-128. doi: 10.1016/j.cell.2009.04.020
    [29] Satoh T, Takeuchi O, Vandenbon A, et al. (2010) The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11: 936-944. doi: 10.1038/ni.1920
    [30] Stender JD, Glass CK (2013) Epigenomic control of the innate immune response. Curr Opin Pharmacol 13: 582-587. doi: 10.1016/j.coph.2013.06.002
    [31] Blackwood EM, Kadonaga JT (1998) Going the distance: a current view of enhancer action. Science 281: 60-63.
    [32] Kaikkonen MU, Spann NJ, Heinz S, et al. (2013) Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell 51: 310-325. doi: 10.1016/j.molcel.2013.07.010
    [33] Pott S, Lieb JD (2015) What are super-enhancers? Nat Genet 47: 8-12.
    [34] Brown JD, Lin CY, Duan Q, et al. (2014) NF-kappaB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 56: 219-231. doi: 10.1016/j.molcel.2014.08.024
    [35] Price AE, Liang HE, Sullivan BM, et al. (2010) Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A 107: 11489-11494. doi: 10.1073/pnas.1003988107
    [36] Monticelli LA, Sonnenberg GF, Abt MC, et al. (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol 12: 1045-1054. doi: 10.1038/ni.2131
    [37] Fuchs A, Vermi W, Lee JS, et al. (2013) Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity 38: 769-781. doi: 10.1016/j.immuni.2013.02.010
    [38] Cella M, Fuchs A, Vermi W, et al. (2009) A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457: 722-725. doi: 10.1038/nature07537
    [39] Buonocore S, Ahern PP, Uhlig HH, et al. (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464: 1371-1375. doi: 10.1038/nature08949
    [40] Goto Y, Ivanov, II (2013) Intestinal epithelial cells as mediators of the commensal-host immune crosstalk. Immunol Cell Biol 91: 204-214. doi: 10.1038/icb.2012.80
    [41] Salzman NH, Underwood MA, Bevins CL (2007) Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin Immunol 19: 70-83. doi: 10.1016/j.smim.2007.04.002
    [42] Fischer N, Sechet E, Friedman R, et al. (2016) Histone deacetylase inhibition enhances antimicrobial peptide but not inflammatory cytokine expression upon bacterial challenge. Proc Natl Acad Sci U S A 113: E2993-3001. doi: 10.1073/pnas.1605997113
    [43] Chookajorn T, Dzikowski R, Frank M, et al. (2007) Epigenetic memory at malaria virulence genes. Proc Natl Acad Sci U S A 104: 899-902. doi: 10.1073/pnas.0609084103
    [44] Huguenin M, Bracha R, Chookajorn T, et al. (2010) Epigenetic transcriptional gene silencing in Entamoeba histolytica: insight into histone and chromatin modifications. Parasitology 137: 619-627. doi: 10.1017/S0031182009991363
    [45] Marazzi I, Ho JS, Kim J, et al. (2012) Suppression of the antiviral response by an influenza histone mimic. Nature 483: 428-433. doi: 10.1038/nature10892
    [46] Pennini ME, Pai RK, Schultz DC, et al. (2006) Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-gamma-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling. J Immunol 176: 4323-4330. doi: 10.4049/jimmunol.176.7.4323
    [47] Lebreton A, Job V, Ragon M, et al. (2014) Structural basis for the inhibition of the chromatin repressor BAHD1 by the bacterial nucleomodulin LntA. MBio 5: e00775-00713.
    [48] Eskandarian HA, Impens F, Nahori MA, et al. (2013) A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection. Science 341: 1238858. doi: 10.1126/science.1238858
    [49] Arbibe L, Kim DW, Batsche E, et al. (2007) An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses. Nat Immunol 8: 47-56. doi: 10.1038/ni1423
    [50] Harouz H, Rachez C, Meijer BM, et al. (2014) Shigella flexneri targets the HP1gamma subcode through the phosphothreonine lyase OspF. EMBO J 33: 2606-2622. doi: 10.15252/embj.201489244
    [51] Li H, Xu H, Zhou Y, et al. (2007) The phosphothreonine lyase activity of a bacterial type III effector family. Science 315: 1000-1003. doi: 10.1126/science.1138960
    [52] Foster SL, Hargreaves DC, Medzhitov R (2007) Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447: 972-978.
    [53] El Gazzar M, Liu T, Yoza BK, et al. (2010) Dynamic and selective nucleosome repositioning during endotoxin tolerance. J Biol Chem 285: 1259-1271. doi: 10.1074/jbc.M109.067330
    [54] Shalova IN, Lim JY, Chittezhath M, et al. (2015) Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1alpha. Immunity 42: 484-498. doi: 10.1016/j.immuni.2015.02.001
    [55] Cheng SC, Scicluna BP, Arts RJ, et al. (2016) Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol 17: 406-413. doi: 10.1038/ni.3398
    [56] Chen J, Ivashkiv LB (2010) IFN-gamma abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling. Proc Natl Acad Sci U S A 107: 19438-19443. doi: 10.1073/pnas.1007816107
    [57] Tribouley J, Tribouley-Duret J, Appriou M (1978) [Effect of Bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni]. C R Seances Soc Biol Fil 172: 902-904.
    [58] Kleinnijenhuis J, Quintin J, Preijers F, et al. (2014) Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun 6: 152-158. doi: 10.1159/000355628
    [59] van 't Wout JW, Poell R, van Furth R (1992) The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand J Immunol 36: 713-719. doi: 10.1111/j.1365-3083.1992.tb03132.x
    [60] Kleinnijenhuis J, Quintin J, Preijers F, et al. (2012) Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 109: 17537-17542. doi: 10.1073/pnas.1202870109
    [61] Quintin J, Saeed S, Martens JH, et al. (2012) Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12: 223-232. doi: 10.1016/j.chom.2012.06.006
    [62] Ostuni R, Piccolo V, Barozzi I, et al. (2013) Latent enhancers activated by stimulation in differentiated cells. Cell 152: 157-171. doi: 10.1016/j.cell.2012.12.018
    [63] Bezman NA, Kim CC, Sun JC, et al. (2012) Molecular definition of the identity and activation of natural killer cells. Nat Immunol 13: 1000-1009. doi: 10.1038/ni.2395
    [64] Schlums H, Cichocki F, Tesi B, et al. (2015) Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42: 443-456. doi: 10.1016/j.immuni.2015.02.008
    [65] Kagi D, Ledermann B, Burki K, et al. (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369: 31-37. doi: 10.1038/369031a0
    [66] Ferlazzo G, Tsang ML, Moretta L, et al. (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195: 343-351. doi: 10.1084/jem.20011149
    [67] Xu HC, Grusdat M, Pandyra AA, et al. (2014) Type I interferon protects antiviral CD8+ T cells from NK cell cytotoxicity. Immunity 40: 949-960. doi: 10.1016/j.immuni.2014.05.004
    [68] Bouchon A, Cella M, Grierson HL, et al. (2001) Activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family. J Immunol 167: 5517-5521. doi: 10.4049/jimmunol.167.10.5517
    [69] Kruse PH, Matta J, Ugolini S, et al. (2014) Natural cytotoxicity receptors and their ligands. Immunol Cell Biol 92: 221-229. doi: 10.1038/icb.2013.98
    [70] Uhrberg M, Valiante NM, Shum BP, et al. (1997) Human diversity in killer cell inhibitory receptor genes. Immunity 7: 753-763. doi: 10.1016/S1074-7613(00)80394-5
    [71] O'Leary JG, Goodarzi M, Drayton DL, et al. (2006) T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat Immunol 7: 507-516. doi: 10.1038/ni1332
    [72] Sun JC, Beilke JN, Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457: 557-561. doi: 10.1038/nature07665
    [73] Min-Oo G, Lanier LL (2014) Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection. J Exp Med 211: 2669-2680. doi: 10.1084/jem.20141172
    [74] Lee J, Zhang T, Hwang I, et al. (2015) Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals. Immunity 42: 431-442. doi: 10.1016/j.immuni.2015.02.013
    [75] Calore F, Lovat F, Garofalo M (2013) Non-coding RNAs and cancer. Int J Mol Sci 14: 17085-17110. doi: 10.3390/ijms140817085
    [76] Nagano T, Fraser P (2011) No-nonsense functions for long noncoding RNAs. Cell 145: 178-181. doi: 10.1016/j.cell.2011.03.014
    [77] Da Sacco L, Baldassarre A, Masotti A (2012) Bioinformatics tools and novel challenges in long non-coding RNAs (lncRNAs) functional analysis. Int J Mol Sci 13: 97-114.
    [78] Wilusz JE, Sunwoo H, Spector DL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 23: 1494-1504. doi: 10.1101/gad.1800909
    [79] Kaikkonen MU, Lam MT, Glass CK (2011) Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc Res 90: 430-440. doi: 10.1093/cvr/cvr097
    [80] Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43: 904-914. doi: 10.1016/j.molcel.2011.08.018
    [81] Ng KW, Anderson C, Marshall EA, et al. (2016) Piwi-interacting RNAs in cancer: emerging functions and clinical utility. Mol Cancer 15: 5. doi: 10.1186/s12943-016-0491-9
    [82] Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281-297. doi: 10.1016/S0092-8674(04)00045-5
    [83] Doench JG, Sharp PA (2004) Specificity of microRNA target selection in translational repression. Genes Dev 18: 504-511. doi: 10.1101/gad.1184404
    [84] Grimson A, Farh KK, Johnston WK, et al. (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27: 91-105. doi: 10.1016/j.molcel.2007.06.017
    [85] Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10: 126-139.
    [86] Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75: 843-854.
    [87] Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75: 855-862. doi: 10.1016/0092-8674(93)90530-4
    [88] Paladini L, Fabris L, Bottai G, et al. (2016) Targeting microRNAs as key modulators of tumor immune response. J Exp Clin Cancer Res 35: 103. doi: 10.1186/s13046-016-0375-2
    [89] Taganov KD, Boldin MP, Chang KJ, et al. (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103: 12481-12486. doi: 10.1073/pnas.0605298103
    [90] O'Neill LA, Sheedy FJ, McCoy CE (2011) MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol 11: 163-175. doi: 10.1038/nri2957
    [91] Pathak S, Grillo AR, Scarpa M, et al. (2015) MiR-155 modulates the inflammatory phenotype of intestinal myofibroblasts by targeting SOCS1 in ulcerative colitis. Exp Mol Med 47: e164. doi: 10.1038/emm.2015.21
    [92] Bazzoni F, Rossato M, Fabbri M, et al. (2009) Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc Natl Acad Sci U S A 106: 5282-5287. doi: 10.1073/pnas.0810909106
    [93] Androulidaki A, Iliopoulos D, Arranz A, et al. (2009) The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31: 220-231. doi: 10.1016/j.immuni.2009.06.024
    [94] Curtale G, Mirolo M, Renzi TA, et al. (2013) Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b. Proc Natl Acad Sci U S A 110: 11499-11504. doi: 10.1073/pnas.1219852110
    [95] McCoy CE, Sheedy FJ, Qualls JE, et al. (2010) IL-10 inhibits miR-155 induction by toll-like receptors. J Biol Chem 285: 20492-20498. doi: 10.1074/jbc.M110.102111
    [96] Rossato M, Curtale G, Tamassia N, et al. (2012) IL-10-induced microRNA-187 negatively regulates TNF-alpha, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci U S A 109: E3101-3110. doi: 10.1073/pnas.1209100109
    [97] Sheedy FJ, Palsson-McDermott E, Hennessy EJ, et al. (2010) Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol 11: 141-147. doi: 10.1038/ni.1828
    [98] El Gazzar M, McCall CE (2010) MicroRNAs distinguish translational from transcriptional silencing during endotoxin tolerance. J Biol Chem 285: 20940-20951. doi: 10.1074/jbc.M110.115063
    [99] El Gazzar M, Church A, Liu T, et al. (2011) MicroRNA-146a regulates both transcription silencing and translation disruption of TNF-alpha during TLR4-induced gene reprogramming. J Leukoc Biol 90: 509-519. doi: 10.1189/jlb.0211074
    [100] Tili E, Michaille JJ, Cimino A, et al. (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179: 5082-5089. doi: 10.4049/jimmunol.179.8.5082
    [101] Renzi TA, Rubino M, Gornati L, et al. (2015) MiR-146b Mediates Endotoxin Tolerance in Human Phagocytes. Mediators Inflamm 2015: 145305.
    [102] Magistri M, Faghihi MA, St Laurent G, 3rd, et al. (2012) Regulation of chromatin structure by long noncoding RNAs: focus on natural antisense transcripts. Trends Genet 28: 389-396. doi: 10.1016/j.tig.2012.03.013
    [103] Louro R, El-Jundi T, Nakaya HI, et al. (2008) Conserved tissue expression signatures of intronic noncoding RNAs transcribed from human and mouse loci. Genomics 92: 18-25. doi: 10.1016/j.ygeno.2008.03.013
    [104] Pandey RR, Mondal T, Mohammad F, et al. (2008) Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell 32: 232-246. doi: 10.1016/j.molcel.2008.08.022
    [105] Wang X, Song X, Glass CK, et al. (2011) The long arm of long noncoding RNAs: roles as sensors regulating gene transcriptional programs. Cold Spring Harb Perspect Biol 3: a003756.
    [106] Guttman M, Rinn JL (2012) Modular regulatory principles of large non-coding RNAs. Nature 482: 339-346. doi: 10.1038/nature10887
    [107] Kretz M, Siprashvili Z, Chu C, et al. (2013) Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 493: 231-235.
    [108] Gong C, Maquat LE (2011) lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements. Nature 470: 284-288. doi: 10.1038/nature09701
    [109] Carpenter S, Aiello D, Atianand MK, et al. (2013) A long noncoding RNA mediates both activation and repression of immune response genes. Science 341: 789-792. doi: 10.1126/science.1240925
    [110] Rapicavoli NA, Qu K, Zhang J, et al. (2013) A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics. Elife 2: e00762.
    [111] Li Z, Chao TC, Chang KY, et al. (2014) The long noncoding RNA THRIL regulates TNFalpha expression through its interaction with hnRNPL. Proc Natl Acad Sci U S A 111: 1002-1007. doi: 10.1073/pnas.1313768111
    [112] Krawczyk M, Emerson BM (2014) p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-kappaB complexes. Elife 3: e01776.
    [113] Liu B, Sun L, Liu Q, et al. (2015) A cytoplasmic NF-kappaB interacting long noncoding RNA blocks IkappaB phosphorylation and suppresses breast cancer metastasis. Cancer Cell 27: 370-381. doi: 10.1016/j.ccell.2015.02.004
    [114] Murphy MB, Medvedev AE (2016) Long noncoding RNAs as regulators of Toll-like receptor signaling and innate immunity. J Leukoc Biol 99: 839-850. doi: 10.1189/jlb.2RU1215-575R
    [115] Li W, Notani D, Rosenfeld MG (2016) Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat Rev Genet 17: 207-223. doi: 10.1038/nrg.2016.4
    [116] Hah N, Murakami S, Nagari A, et al. (2013) Enhancer transcripts mark active estrogen receptor binding sites. Genome Res 23: 1210-1223. doi: 10.1101/gr.152306.112
    [117] Melgar MF, Collins FS, Sethupathy P (2011) Discovery of active enhancers through bidirectional expression of short transcripts. Genome Biol 12: R113. doi: 10.1186/gb-2011-12-11-r113
    [118] Zhu Y, Sun L, Chen Z, et al. (2013) Predicting enhancer transcription and activity from chromatin modifications. Nucleic Acids Res 41: 10032-10043. doi: 10.1093/nar/gkt826
    [119] Arner E, Daub CO, Vitting-Seerup K, et al. (2015) Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347: 1010-1014. doi: 10.1126/science.1259418
    [120] Hah N, Benner C, Chong LW, et al. (2015) Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs. Proc Natl Acad Sci U S A 112: E297-302. doi: 10.1073/pnas.1424028112
    [121] Kim TK, Hemberg M, Gray JM, et al. (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465: 182-187. doi: 10.1038/nature09033
    [122] Alexopoulou L, Holt AC, Medzhitov R, et al. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413: 732-738. doi: 10.1038/35099560
    [123] Lee J, Sayed N, Hunter A, et al. (2012) Activation of innate immunity is required for efficient nuclear reprogramming. Cell 151: 547-558. doi: 10.1016/j.cell.2012.09.034
    [124] Takahashi K, Tanabe K, Ohnuki M, et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861-872. doi: 10.1016/j.cell.2007.11.019
    [125] Takahashi K, Okita K, Nakagawa M, et al. (2007) Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc 2: 3081-3089. doi: 10.1038/nprot.2007.418
    [126] Meng S, Zhou G, Gu Q, et al. (2016) Transdifferentiation Requires iNOS Activation: Role of RING1A S-Nitrosylation. Circ Res 119: e129-e138.
    [127] Buenrostro JD, Giresi PG, Zaba LC, et al. (2013) Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods 10: 1213-1218. doi: 10.1038/nmeth.2688
    [128] Mercer TR, Edwards SL, Clark MB, et al. (2013) DNase I-hypersensitive exons colocalize with promoters and distal regulatory elements. Nat Genet 45: 852-859. doi: 10.1038/ng.2677
    [129] Nagano T, Lubling Y, Yaffe E, et al. (2015) Single-cell Hi-C for genome-wide detection of chromatin interactions that occur simultaneously in a single cell. Nat Protoc 10: 1986-2003. doi: 10.1038/nprot.2015.127
    [130] Miyanari Y, Torres-Padilla ME (2012) Control of ground-state pluripotency by allelic regulation of Nanog. Nature 483: 470-473. doi: 10.1038/nature10807
    [131] Soucie EL, Weng Z, Geirsdottir L, et al. (2016) Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells. Science 351: aad5510. doi: 10.1126/science.aad5510
    [132] Paul F, Arkin Y, Giladi A, et al. (2015) Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors. Cell 163: 1663-1677. doi: 10.1016/j.cell.2015.11.013
    [133] Abraham BJ, Cui K, Tang Q, et al. (2013) Dynamic regulation of epigenomic landscapes during hematopoiesis. BMC Genomics 14: 193. doi: 10.1186/1471-2164-14-193
    [134] Olsson A, Venkatasubramanian M, Chaudhri VK, et al. (2016) Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature 537: 698-702. doi: 10.1038/nature19348
    [135] Epelman S, Lavine KJ, Beaudin AE, et al. (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40: 91-104. doi: 10.1016/j.immuni.2013.11.019
    [136] Italiani P, Boraschi D (2014) From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation. Front Immunol 5: 514.
    [137] Ganan-Gomez I, Wei Y, Starczynowski DT, et al. (2015) Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia 29: 1458-1469. doi: 10.1038/leu.2015.69
    [138] Lin CY, Loven J, Rahl PB, et al. (2012) Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151: 56-67. doi: 10.1016/j.cell.2012.08.026
    [139] Liu G, Gramling S, Munoz D, et al. (2011) Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk. Oncogene 30: 3295-3304. doi: 10.1038/onc.2011.81
    [140] Kawauchi S, Calof AL, Santos R, et al. (2009) Multiple organ system defects and transcriptional dysregulation in the Nipbl(+/-) mouse, a model of Cornelia de Lange Syndrome. PLoS Genet 5: e1000650. doi: 10.1371/journal.pgen.1000650
    [141] Ballman KV (2015) Biomarker: Predictive or Prognostic? J Clin Oncol 33: 3968-3971. doi: 10.1200/JCO.2015.63.3651
    [142] Mehta S, Shelling A, Muthukaruppan A, et al. (2010) Predictive and prognostic molecular markers for cancer medicine. Ther Adv Med Oncol 2: 125-148. doi: 10.1177/1758834009360519
    [143] van Leeuwen MA, Westra J, Limburg PC, et al. (1995) Clinical significance of interleukin-6 measurement in early rheumatoid arthritis: relation with laboratory and clinical variables and radiological progression in a three year prospective study. Ann Rheum Dis 54: 674-677. doi: 10.1136/ard.54.8.674
    [144] Knudsen LS, Klarlund M, Skjodt H, et al. (2008) Biomarkers of inflammation in patients with unclassified polyarthritis and early rheumatoid arthritis. Relationship to disease activity and radiographic outcome. J Rheumatol 35: 1277-1287.
    [145] Klein-Wieringa IR, van der Linden MP, Knevel R, et al. (2011) Baseline serum adipokine levels predict radiographic progression in early rheumatoid arthritis. Arthritis Rheum 63: 2567-2574. doi: 10.1002/art.30449
    [146] Lard LR, Roep BO, Toes RE, et al. (2004) Enhanced concentrations of interleukin 16 are associated with joint destruction in patients with rheumatoid arthritis. J Rheumatol 31: 35-39.
    [147] Syversen SW, Goll GL, Haavardsholm EA, et al. (2008) A high serum level of eotaxin (CCL 11) is associated with less radiographic progression in early rheumatoid arthritis patients. Arthritis Res Ther 10: R28. doi: 10.1186/ar2381
    [148] Irizarry RA, Ladd-Acosta C, Wen B, et al. (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41: 178-186. doi: 10.1038/ng.298
    [149] Laird PW (2003) The power and the promise of DNA methylation markers. Nat Rev Cancer 3: 253-266. doi: 10.1038/nrc1045
    [150] Luczak MW, Jagodzinski PP (2006) The role of DNA methylation in cancer development. Folia Histochem Cytobiol 44: 143-154.
    [151] Lu H, Liu X, Deng Y, et al. (2013) DNA methylation, a hand behind neurodegenerative diseases. Front Aging Neurosci 5: 85.
    [152] Richardson B, Scheinbart L, Strahler J, et al. (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33: 1665-1673. doi: 10.1002/art.1780331109
    [153] Liu Y, Aryee MJ, Padyukov L, et al. (2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol 31: 142-147. doi: 10.1038/nbt.2487
    [154] Lin SY, Hsieh SC, Lin YC, et al. (2012) A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity. Genes Immun 13: 214-220. doi: 10.1038/gene.2011.74
    [155] Yeung KS, Chung BH, Choufani S, et al. (2017) Genome-Wide DNA Methylation Analysis of Chinese Patients with Systemic Lupus Erythematosus Identified Hypomethylation in Genes Related to the Type I Interferon Pathway. PLoS One 12: e0169553. doi: 10.1371/journal.pone.0169553
    [156] Hashimoto Y, Zumwalt TJ, Goel A (2016) DNA methylation patterns as noninvasive biomarkers and targets of epigenetic therapies in colorectal cancer. Epigenomics 8: 685-703. doi: 10.2217/epi-2015-0013
    [157] Uhl B, Gevensleben H, Tolkach Y, et al. (2017) PITX2 DNA Methylation as Biomarker for Individualized Risk Assessment of Prostate Cancer in Core Biopsies. J Mol Diagn 19: 107-114. doi: 10.1016/j.jmoldx.2016.08.008
    [158] Lofton-Day C, Model F, Devos T, et al. (2008) DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem 54: 414-423. doi: 10.1373/clinchem.2007.095992
    [159] Yang M, Park JY (2012) DNA methylation in promoter region as biomarkers in prostate cancer. Methods Mol Biol 863: 67-109. doi: 10.1007/978-1-61779-612-8_5
    [160] Chung W, Kwabi-Addo B, Ittmann M, et al. (2008) Identification of novel tumor markers in prostate, colon and breast cancer by unbiased methylation profiling. PLoS One 3: e2079. doi: 10.1371/journal.pone.0002079
    [161] Jiao Y, Shi C, Edil BH, et al. (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331: 1199-1203. doi: 10.1126/science.1200609
    [162] Dalgliesh GL, Furge K, Greenman C, et al. (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463: 360-363. doi: 10.1038/nature08672

    © 2017 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (
  • Reader Comments
通讯作者: 陈斌,
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索


Article views(2600) PDF downloads(1475) Cited by(1)

Article outline

Figures and Tables

Figures(4)  /  Tables(2)


DownLoad:  Full-Size Img  PowerPoint