Abstract
Epigenetics regulate gene function without any alteration in the DNA sequence. The epigenetics represent one of the most important regulators in different cellular processes and have initially been developed in microorganisms as a protective strategy. The evaluation of the epigenetic mechanisms is also important in achieving an efficient control strategy in tuberculosis (TB). TB is one of the most significant epidemiological concerns in human history. Despite several in vivo and in vitro studies that have evaluated different epigenetic modifications in TB, many aspects of the association between epigenetics and TB are not fully understood. The current paper is aimed at reviewing our knowledge on histone modifications and DNA methylation modifications, as well as miRNAs regulation in TB.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Epigenetics, epistasis and epidemics. Evol. Med. Public Health 2013(1), 86–88 (2013).
- 2. . The epigenotype. Int. J. Epidemiol. 41(1), 10–13 (2011).
- 3. . Pathogens hijack the epigenome: a new twist on host-pathogen interactions. Am. J. Pathol. 184(4), 897–911 (2014).
- 4. . Understanding the Host Epigenetics in Mycobacterium tuberculosis. J. Infect. Dis. 2, 016 (2015). • This opinion study comprehensively provides a clear basis of epigenetic modifications that occur in the host upon tuberculosis (TB) infection and elaborates how Mycobacterium tuberculosis modulates the host epigenome.
- 5. . Environment, epigenetics and neurodegeneration: focus on nutrition in Alzheimer’s disease. Exp. Gerontol. 68, 8–12 (2015).
- 6. . DNA methylation as clinically useful biomarkers-light at the end of the tunnel. Pharmaceuticals 5(1), 94–113 (2012).
- 7. . The role of epigenetics in tuberculosis infection. Epigenomics 8(4), 537–549 (2016). • Authors discuss the principles and advances in induced epigenetic modifications upon TB infection and their effects on the host immune responses. They anticipated host susceptibility to Mycobacterium tuberculosis is critical for disease progression because of its epigenetic predisposition.
- 8. . Microbiota impact on the epigenetic regulation of colorectal cancer. Trends Mol. Med. 19(12), 714–725 (2013).
- 9. Genomic plasticity between human and mycobacterial DNA: a review. Tuberculosis 107, 38–47 (2017).
- 10. . Diet, the gut microbiome, and epigenetics. Cancer J. 20(3), 170 (2014).
- 11. World Health Organization. Global tuberculosis report 2018. (2018). www.who.int/tb/publications/global_report/en/
- 12. . Whole genome DNA methylation analysis of active pulmonary tuberculosis disease identifies novel epigenetic signatures. Am. J. Respir. Crit. Care Med. 197, 4321 (2018). •• An important original paper which hypothesized DNA methylation pattern may contribute to TB severity and development of its systemic symptoms.
- 13. The human microbiota in pulmonary tuberculosis: not so innocent bystanders. Tuberculosis 113, 215–221 (2018).
- 14. . Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-γ-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling. J. Immunol. 176(7), 4323–4330 (2006).
- 15. Identification of a novel role of ESAT‐6‐dependent miR‐155 induction during infection of macrophages with Mycobacterium tuberculosis. Cell. Microbiol. 14(10), 1620–1631 (2012).
- 16. . Mycobacteria inhibition of IFN-γ induced HLA-DR gene expression by up-regulating histone deacetylation at the promoter region in human THP-1 monocytic cells. J. Immunol. 174(9), 5687–5694 (2005).
- 17. . Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3. Nat. Commun. 6, 8922 (2015).
- 18. Hypothetical protein Rv3423.1 of Mycobacterium tuberculosis is a histone acetyltransferase. FEBS J. 283(2), 265–281 (2016).
- 19. . The interaction of mycobacterial protein Rv2966c with host chromatin is mediated through non-CpG methylation and histone H3/H4 binding. Nucleic Acids Res. 43(8), 3922–3937 (2015). • This original research explores the role of Rv2966c in DNA methylation modulating in the host cells. Authors addressed that while CpG methylation is introduced as the normal mode of DNA methylation, Rv2966c may induce methylation in non-CpG sites upon TB infection.
- 20. . Mycobacterium tuberculosis infection induces HDAC1-mediated suppression of IL-12B gene expression in macrophages. Front. Cell. Infect. Microbiol. 5, 90 (2015).
- 21. . Mycobacterium tuberculosis EIS gene inhibits macrophage autophagy through up-regulation of IL-10 by increasing the acetylation of histone H3. Biochem. Biophys. Res. Commun. 473(4), 1229–1234 (2016).
- 22. Alu repeats as transcriptional regulatory platforms in macrophage responses to M. tuberculosis infection. Nucleic Acids Res. 44(22), 10571–10587 (2016).
- 23. Mycobacterium tuberculosis EsxL inhibits MHC-II expression by promoting hypermethylation in class-II transactivator loci in macrophages. J. Biol. Chem. 292(17), 6855–6868 (2017).
- 24. . Epigenetic regulation of matrix metalloproteinase-1 and-3 expression in Mycobacterium tuberculosis infection. Front. Immunol. 8, 602 (2017).
- 25. . Histone methyltransferase SET8 epigenetically reprograms host immune responses to assist mycobacterial survival. J. Infect. Dis. 216(4), 477–488 (2017).
- 26. . Mycobacterium tuberculosis infection induces IL-10 gene expression by disturbing histone deacetylase 6 and histonedeacetylase 11 equilibrium in macrophages. Tuberculosis (Edinb) 108, 118–123 (2018).
- 27. . Lysine acetylation of the Mycobacterium tuberculosis HU protein modulates its DNA binding and genome organization. Mol. Microbiol. 100(4), 577–588 (2016).
- 28. . A Sir2 family protein Rv1151c deacetylates HU to alter its DNA binding mode in Mycobacterium tuberculosis. Biochem. Biophys. Res. Commun. 493(3), 1204–1209 (2017).
- 29. . Histone methyltransferase SUV39H1 participates in host defense by methylating mycobacterial histone-like protein HupB. EMBO J. 37(2), 183–200 (2018).
- 30. Acetylation by Eis and deacetylation by Rv1151c of Mycobacterium tuberculosis HupB: biochemical and structural insight. Biochemistry 57(5), 781–790 (2018).
- 31. Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res. 25(12), 1801–1811 (2015).
- 32. Unraveling methylation changes of host macrophages in Mycobacterium tuberculosis infection. Tuberculosis 98, 139–148 (2016).
- 33. Genome-wide non-CpG methylation of the host genome during M. tuberculosis infection. Sci. Rep. 6, 25006 (2016). • An important original research that indicates association of genome-wide non-CpG DNA methylation and modulating host gene expression upon TB infection.
- 34. NLRP3 activation was regulated by DNA methylation modification during Mycobacterium tuberculosis infection. Biomed. Res. Int. 2016, 1–10 (2016).
- 35. CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22. Exp. Mol. Med. 50(5), 62 (2018).
- 36. Gene activation precedes DNA demethylation in response to infection in human dendritic cells. Proc. Natl Acad. Sci. USA 116(14), 6938–6943 (2019). • This paper highlights the importance of whole genome DNA methylation landscape of human dendritic cells upon TB infection.
- 37. . Vitamin D receptor gene methylation is associated with ethnicity, tuberculosis, and TaqI polymorphism. Hum. Immunol. 72(3), 262–268 (2011).
- 38. Aberrant Toll-like receptor 2 promoter methylation in blood cells from patients with pulmonary tuberculosis. J. Infect. 69(6), 546–557 (2014).
- 39. Involvement of cytochrome P450 1A1 and glutathione S-transferase P1 polymorphisms and promoter hypermethylation in the progression of anti-tuberculosis drug-induced liver injury: a case–control study. PloS ONE 10(3), e0119481 (2015).
- 40. Epigenetics and proteomics join transcriptomics in the quest for tuberculosis biomarkers. MBio 6(5), e01187–e01115 (2015).
- 41. Correlation of CpG Island methylation of the cytochrome P450 2E1/2D6 genes with liver injury induced by anti-tuberculosis drugs: a nested case–control study. Int. J. Environ. Res. Public Health 13(8), 776 (2016).
- 42. The methylation state of VDR gene in pulmonary tuberculosis patients. J. Thorac. Dis. 9(11), 4353 (2017).
- 43. Vitamin D and the promoter methylation of its metabolic pathway genes in association with the risk and prognosis of tuberculosis. Clin. Epigenetics 10(1), 118 (2018).
- 44. Schistosomiasis induces persistent DNA methylation and tuberculosis-specific immune changes. J. Immunol. 201(1), 124–133 (2018).
- 45. . Methylation status of alu repetitive elements in children with tuberculosis disease. Int. J. Mycobacteriol. 7(3), 242 (2018).
- 46. . Assessment of global DNA methylation in children with tuberculosis disease. Int. J. Mycobacteriol. 7(4), 338 (2018).
- 47. . Histone modifications and chromatin remodeling during bacterial infections. Cell Host Microbe 4(2), 100–109 (2008).
- 48. . Higher-order structures of chromatin: the elusive 30 nm fiber. Cell 128(4), 651–654 (2007).
- 49. . Composition and functional specificity of SWI2/SNF2 class chromatin remodeling complexes. Biochim. Biophys. Acta 1681(2–3), 59–73 (2005).
- 50. . Chromatin modifications and their function. Cell 128(4), 693–705 (2007).
- 51. . Indications to epigenetic dysfunction in the pathogenesis of common variable immunodeficiency. Arch. Immunol. Ther. Exp. 65(2), 101–110 (2017).
- 52. . ESAT6 differentially inhibits IFN‐γ‐inducible class II transactivator isoforms in both a TLR2‐dependent and‐independent manner. Immunol. Cell Biol. 90(4), 411–420 (2012).
- 53. . Commercially available, FDA-approved epigenetic modifiers as therapeutic agents in bacterial infection. Antiinflamm. Antiallergy. Drug 2(1), 79–88 (2015).
- 54. Histone H3K14 hypoacetylation and H3K27 hypermethylation along with HDAC1 up-regulation and KDM6B down-regulation are associated with active pulmonary tuberculosis disease. Am. J. Transl. Res. 9(4), 1943 (2017).
- 55. . Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu. Rev. Biochem. 75, 243–269 (2006).
- 56. . C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB. Immunity 26(5), 605–616 (2007).
- 57. . The 19kDa Mycobacterium tuberculosis lipoprotein (LpqH) induces macrophage apoptosis through extrinsic and intrinsic pathways: a role for the mitochondrial apoptosis-inducing factor. Clin. Dev. Immunol. 2012, 950503 (2012).
- 58. Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7. Proc. Natl Acad. Sci. USA 109(20), 7729–7734 (2012).
- 59. . Characterization of a novel acetyltransferase found only in pathogenic strains of Mycobacterium tuberculosis. University of Alabama, Birmingham, Alabama, USA (2007). Google Scholar
- 60. . Matrix metalloproteinase-1 expression in tuberculosis is regulated by histone acetylation: p2151. Clin. Microbiol. Infect. 18, 626–627 (2012).
- 61. . CpG islands and the regulation of transcription. Genes Dev. 25(10), 1010–1022 (2011).
- 62. . Mammalian epigenetic mechanisms. IUBMB Life 66(4), 240–256 (2014). •• An important review in this field discussing the different layers of epigenetic modifications and their role in various cellular processes in eukaryotic cells.
- 63. . The ‘golden age’of DNA methylation in neurodegenerative diseases. Clin. Chem. Lab. Med. 51(3), 523–534 (2013).
- 64. . Mammalian DNA methyltransferases. Acta Biochim. Pol. 53(2), 245 (2006).
- 65. . Genomic DNA methylation: the mark and its mediators. Trends Biochem. Sci. 31(2), 89–97 (2006).
- 66. . CpG islands–‘a rough guide’. FEBS Lett. 583(11), 1713–1720 (2009).
- 67. . S-adenosylhomocysteine hydrolase participates in DNA methylation inheritance. J. Mol. Biol. 430(14), 2051–2065 (2018).
- 68. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6(6), 692–702 (2011).
- 69. Early demethylation of non-CpG, CpC-rich, elements in the myogenin 5’-flanking region: a priming effect on the spreading of active demethylation? Cell Cycle 9(19), 3965–3976 (2010).
- 70. . A reassessment of semiquantitative analytical procedures for DNA methylation: comparison of bisulfite-and HpaII polymerase-chain-reaction-based methods. Anal. Biochem. 350(1), 24–31 (2006).
- 71. N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 113(31), E4523–E4530 (2016).
- 72. . Regulation of expression and activity of DNA (cytosine-5) methyltransferases in mammalian cells. Prog. Mol. Biol. Transl. Sci. 101, 311–333 (2011).
- 73. . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3), 247–257 (1999).
- 74. . Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat. Genet. 19(3), 219 (1998).
- 75. . Disclosing bias in bisulfite assay: methPrimers underestimate high DNA methylation. PLoS ONE 10(2), e0118318 (2015). • A research study that addresses the aberrant DNA methylation more largely induced at the low CpG density regions rather than high CpG density upon TB infection.
- 76. . Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129(8), 1983–1993 (2002).
- 77. Mechanism and biological role of Dnmt2 in nucleic acid methylation. Trends Biochem. Sci. 14(9), 1108–1123 (2017).
- 78. . Cytosine methylation by DNMT2 facilitates stability and survival of HIV-1 RNA in the host cell during infection. Biochem. J. 474(12), 2009–2026 (2017).
- 79. DNA methylation impacts gene expression and ensures hypoxic survival of Mycobacterium tuberculosis. PLoS. Pathog. 9(7), e1003419 (2013).
- 80. . The role of epigenetics, bacterial and host factors in progression of Mycobacterium tuberculosis infection. Tuberculosis 113, 200–214 (2018). •• A review study with a brief discussion about various mechanisms, as well as epigenetics, employed during TB infection to suppress host immune system.
- 81. . The human leukemia cell line, THP-1: a multifacetted model for the study of monocyte–macrophage differentiation. Experientia 47(1), 22–31 (1991).
- 82. . Mycobacterium tuberculosis and the macrophage: maintaining a balance. Cell Host Microbe 3(6), 399–407 (2008).
- 83. . The role of dendritic cells in Mycobacterium tuberculosis infection. Virulence 3(7), 654–659 (2012).
- 84. . Genetic-and-epigenetic interspecies networks for cross-talk mechanisms in human macrophages and dendritic cells during MTB infection. Front. Cell. Infect. Microbiol. 6, 124 (2016).
- 85. . Epigenetics and trained immunity. Antioxid. Redox Signal. 29(11), 1023–1040 (2018).
- 86. . A lasting impression: epigenetic memory of bacterial infections? Cell Host Microbe 19(5), 579–582 (2016).
- 87. . DNA methylation in bacteria: from the methyl group to the methylome. Curr. Opin. Microbiol. 25, 9–16 (2015).
- 88. . Antibiotic methylation: a new mechanism of antimicrobial resistance. Trends Microbiol. 24(10), 771–772 (2016). •• A new study on a novel mode of tuberculosis drug resistance by epigenetic mechanisms.
- 89. . Epigenetics in immune-mediated pulmonary diseases. Clin. Rev. Allergy Immunol. 45(3), 314–330 (2013).
- 90. . RNA polymerase III transcribes human microRNAs. Nat. Struct. Mol. Biol. 13(12), 1097 (2006).
- 91. . Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10(12), 1957–1966 (2004).
- 92. Identification of hundreds of conserved and nonconserved human microRNAs. Nat. Genet. 37(7), 766 (2005).
- 93. Comparative miRNA expression profiles in individuals with latent and active tuberculosis. PloS ONE 6(10), e25832 (2011).
- 94. . Inductive microRNA‐21 impairs anti‐mycobacterial responses by targeting IL‐12 and Bcl‐2. FEBS Lett. 586(16), 2459–2467 (2012).
- 95. . Mycobacterium tuberculosis decreases human macrophage IFN-γ responsiveness through miR-132 and miR-26a. J. Immunol. 193(9), 4537–4547 (2014).
- 96. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ. Nat. Immunol. 12(9), 861 (2011).
- 97. Mycobacterium tuberculosis controls microRNA-99b (miR-99b) expression in infected murine dendritic cells to modulate host immunity. J. Biol. Chem. 288(7), 5056–5061 (2013).
- 98. Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b. Proc. Natl Acad. Sci. USA 108(42), 17408–17413 (2011).
- 99. . Modulation of T cell cytokine production by miR-144* with elevated expression in patients with pulmonary tuberculosis. Mol. Immunol. 48(9–10), 1084–1090 (2011).
- 100. . MicroRNA-146a represses mycobacteria-induced inflammatory response and facilitates bacterial replication via targeting IRAK-1 and TRAF-6. PloS ONE 8(12), e81438148 (2013).
- 101. . Altered microRNA signatures in sputum of patients with active pulmonary tuberculosis. PloS ONE 7(8), e43184 (2012). •• For the first time, the profile of miRNA expression in sputum was evaluated during TB infection. The important role of miRNAs in the pathonegenesis, diagnosis and prognosis of TB infection is confirmed.
- 102. Regulation of the germinal center response by microRNA-155. Science 316(5824), 604–608 (2007).
- 103. Analysis of microRNA expression profiling identifies miR-155 and miR-155* as potential diagnostic markers for active tuberculosis: a preliminary study. Hum. Immunol. 73(1), 31–37 (2012).
- 104. MyD88 as a target of microRNA-203 in regulation of lipopolysaccharide or Bacille Calmette-Guerin induced inflammatory response of macrophage RAW264. 7 cells. Cell. Mol. Immunol. 55(3–4), 303–309 (2013).
- 105. MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. J. Clin. Investig. 123(11), 4836–4848 (2013).
- 106. Altered microRNA expression levels in mononuclear cells of patients with pulmonary and pleural tuberculosis and their relation with components of the immune response. Cell. Mol. Immunol. 53(3), 265–269 (2013).
- 107. MicroRNA let-7 modulates the immune response to Mycobacterium tuberculosis infection via control of A20, an inhibitor of the NF-κB pathway. Cell Host Microbe 17(3), 345–356 (2015).
- 108. . Are microRNAs suitable biomarkers of immunity to tuberculosis? Mol. Cell. Probes 1(1), 8 (2014).