Epigenetic drug discovery: Breaking through the immune barrier

Nature Reviews Drug Discovery

Volumn 15, Issue 12, 2016, Pages 835-853

  Tough, David F ^a   Tak, Paul P ^b   Tarakhovsky, Alexander ^c   Prinjha, Rab K ^a  

^a Cell Biology Unit   (United Kingdom)

^b GLAXOSMITHKLINE   (United Kingdom)

^c ROCKEFELLER UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 METHOXY N (1,2,3,4 TETRAHYDRO 3 METHYL 2 OXO 6 QUINAZOLINYL)BENZENESULFONAMIDE; 4 (4 CHLOROPHENYL) 2,3,9 TRIMETHYL 6H THIENO[3,2 F][1,2,4]TRIAZOLO[4,3 A][1,4]DIAZEPINE 6 ACETIC ACID TERT BUTYL ESTER; 6 (4 CHLOROPHENYL) N ETHYL 8 METHOXY 1 METHYL 4H [1,2,4]TRIAZOLO[4,3 A][1,4]BENZODIAZEPINE 4 ACETAMIDE; 7 (3,5 DIMETHYL 4 ISOXAZOLYL) 1,3 DIHYDRO 8 METHOXY 1 [1 (2 PYRIDINYL)ETHYL] 2H IMIDAZO[4,5 C]QUINOLIN 2 ONE; APABETALONE; AZACITIDINE; B7 ANTIGEN; BROMODOMAIN INHIBITOR; CD40 ANTIGEN; DECITABINE; DNA METHYLTRANSFERASE; DNA METHYLTRANSFERASE INHIBITOR; GIVINOSTAT; GSK 503; HISTONE DEACETYLASE; HISTONE DEACETYLASE INHIBITOR; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 23; LYSINE METHYLTRANSFERASE INHIBITOR; METHYLTRANSFERASE INHIBITOR; NW 21; ROMIDEPSIN; SIRT 2104; TRANSCRIPTION FACTOR FOXP3; TUBASTATIN; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALPROIC ACID; VORINOSTAT;

AUTOIMMUNE DISEASE; CELL FATE; CELL FUNCTION; DNA METHYLATION; DNA MODIFICATION; DRUG DEVELOPMENT; DRUG TARGETING; ENVIRONMENT; EPIGENETICS; GENE EXPRESSION REGULATION; GENETIC TRANSCRIPTION; GENETICS; HEREDITY; HISTONE MODIFICATION; HUMAN; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; IMMUNOPATHOLOGY; INFECTION; INFLAMMATORY DISEASE; LIFESTYLE; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; ANIMAL; AUTOIMMUNE DISEASES; GENETIC EPIGENESIS; INFLAMMATION;

ANIMALS; AUTOIMMUNE DISEASES; DRUG DISCOVERY; EPIGENESIS, GENETIC; HUMANS; INFLAMMATION;

EID: 84992035151     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd.2016.185     Document Type: Review

References (231)

1. Meng H., et al. DNA methylation, its mediators and genome integrity. Int. J. Biol. Sci. 11, 604-617 (2015
2. Schultz M. D., et al. Human body epigenome maps reveal noncanonical DNA methylation variation. Nature 523, 212-216 (2015); corrigendum 530, 242 (2016
3. Schmidl C., et al. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res. 19, 1165-1174 (2009
4. Lister R., et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315-322 (2009
5. Laurent L., et al. Dynamic changes in the human methylome during differentiation. Genome Res. 20, 320-331 (2010
6. Zhang Y., et al. DNA methylation analysis of chromosome 21 gene promoters at single base pair and single allele resolution. PLoS Genet. 5, e1000438 2009
7. Campanero M. R., Armstrong M. I., & Flemington E. K. CpG methylation as a mechanism for the regulation of E2F activity. Proc. Natl Acad. Sci. USA 97, 6481-6486 (2000
8. Iguchi-Ariga S. M., & Schaffner W. CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. Genes Dev. 3, 612-619 (1989
9. Phillips J. E., & Corces V. G. CTCF: master weaver of the genome. Cell 137, 1194-1211 (2009
10. Bell A. C., & Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482-485 (2000
11. Filippova G. N., et al. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat. Genet. 28, 335-343 (2001
12. Hark A. T., et al. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405, 486-489 (2000
13. Jones P. L., et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19, 187-191 (1998
14. Nan X., et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386-389 (1998
15. Tahiliani M., et al. Conversion of 5 methylcytosine to 5 hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930-935 (2009
16. He Y. F., et al. Tet-mediated formation of 5 carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303-1307 (2011
17. Ito S., et al. Tet proteins can convert 5 methylcytosine to 5 formylcytosine and 5 carboxylcytosine. Science 333, 1300-1303 (2011
18. Cortellino S., et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146, 67-79 (2011
19. Maiti A., & Drohat A. C. Thymine DNA glycosylase can rapidly excise 5 formylcytosine and 5 carboxylcytosine: potential implicatons for active demethylation of CpG sites. J. Biol. Chem. 286, 35334-35338 (2011
20. Zhou T., et al. Structural basis for hydroxymethylcytosine recognition by the SRA domain of UHRF2. Mol. Cell 54, 879-886 (2014
21. Yu M., et al. Base-resolution analysis of 5 hydroxymethylcytosine in the mammalian genome. Cell 149, 1368-1380 (2012
22. Pastor W. A., et al. Genome-wide mapping of 5 hydroxymethylcytosine in embryonic stem cells. Nature 473, 394-397 (2011
23. Ficz G., et al. Dynamic regulation of 5 hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398-402 (2011
24. Stroud H., Feng S., Morey Kinney S., Pradhan S., & Jacobsen S. E. 5 Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol. 12, R54 2011
25. Szulwach K. E., et al. Integrating 5 hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet. 7, e1002154 2011
26. Hon G., et al. 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol. Cell 56, 286-297 (2014
27. Marina R. J., et al. TET-catalyzed oxidation of intragenic 5 methylcytosine regulates CTCF-dependent alternative splicing. EMBO J. 35, 335-355 (2015
28. Davey C. A., Sargent D. F., Luger K., Maeder A. W., & Richmond T. J. Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 Å resolution. J. Mol. Biol. 319, 1097-1113 (2002
29. Luger K., Mader A. W., Richmond R. K., Sargent D. F., & Richmond T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251-260 (1997
30. Talbert P. B., & Henikoff S. Histone variants-ancient wrap artists of the epigenome. Nat. Rev. Mol. Cell Biol. 11, 264-275 (2010
31. Hong L., Schroth G. P., Matthews H. R., Yau P., & Bradbury E. M. Studies of the DNA binding properties of histone H4 amino terminus. Thermal denaturation studies reveal that acetylation markedly reduces the binding constant of the H4 tail to DNA. J. Biol. Chem. 268, 305-314 (1993
32. Zeng L., & Zhou M. M. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 513, 124-128 (2002
33. Kouzarides T. Chromatin modifications and their function. Cell 128, 693-705 (2007
34. Taverna S. D., Li H., Ruthenburg A. J., Allis C. D., & Patel D. J. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat. Struct. Mol. Biol. 14, 1025-1040 (2007
35. Janeway C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1-13 (1989
36. Matzinger P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991-1045 (1994
37. Ramsey S. A., et al. Uncovering a macrophage transcriptional program by integrating evidence from motif scanning and expression dynamics. PLoS Comput. Biol. 4, e1000021 2008
38. Kittan N. A., et al. Cytokine induced phenotypic and epigenetic signatures are key to establishing specific macrophage phenotypes. PLoS ONE 8, e78045 2013
39. Ramirez-Carrozzi V. R., et al. Selective and antagonistic functions of SWI/SNF and Mi 2β nucleosome remodeling complexes during an inflammatory response. Genes Dev. 20, 282-296 (2006
40. Kaikkonen M. U., et al. Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol. Cell 51, 310-325 (2013
41. Ostuni R., et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157-171 (2013
42. Netea M. G., Quintin J., & van der Meer J. W. Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355-361 (2011
43. Palmer E. The cell antigen receptor: a logical response to an unknown ligand. J. Recept. Signal Transduct. Res. 26, 367-378 (2006
44. van Noesel C. J., & van Lier R. A. Architecture of the human B cell antigen receptors. Blood 82, 363-373 (1993
45. Avni O., et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat. Immunol. 3, 643-651 (2002
46. Koyanagi M., et al. EZH2 and histone 3 trimethyl lysine 27 associated with Il4 and Il13 gene silencing in TH1 cells. J. Biol. Chem. 280, 31470-31477 (2005
47. Winders B. R., Schwartz R. H., & 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. 173, 7377-7384 (2004
48. Akimzhanov A. M., Yang X. O., & Dong C. Chromatin remodeling of interleukin 17 (IL 17)-IL 17F cytokine gene locus during inflammatory helper T cell differentiation. J. Biol. Chem. 282, 5969-5972 (2007
49. Chang S., & Aune T. M. Dynamic changes in histone-methylation 'marks' across the locus encoding interferon-γ during the differentiation of T helper type 2 cells. Nat. Immunol. 8, 723-731 (2007
50. Wei G., et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155-167 (2009
51. Ichiyama K., et al. The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity 42, 613-626 (2015
52. Kersh E. N., et al. Rapid demethylation of the IFN γ gene occurs in memory but not naive CD8 T cells. J. Immunol. 176, 4083-4093 (2006
53. Zediak V. P., Johnnidis J. B., Wherry E. J., & Berger S. L. Cutting edge: persistently open chromatin at effector gene loci in resting memory CD8+ T cells independent of transcriptional status. J. Immunol. 186, 2705-2709 (2011
54. Syrbe U., et al. Differential regulation of P selectin ligand expression in naive versus memory CD4+ T cells: evidence for epigenetic regulation of involved glycosyltransferase genes. Blood 104, 3243-3248 (2004
55. Steinfelder S., et al. Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells. Blood 117, 2839-2846 (2011
56. Fitzpatrick D. R., Shirley K. M., & Kelso A. Cutting edge: stable epigenetic inheritance of regional IFN γ promoter demethylation in CD44highCD8+ T lymphocytes. J. Immunol. 162, 5053-5057 (1999
57. Messi M., et al. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. Nat. Immunol. 4, 78-86 (2003
58. Yamashita M., et al. Interleukin (IL)-4 independent maintenance of histone modification of the IL 4 gene loci in memory Th2 cells. J. Biol. Chem. 279, 39454-39464 (2004
59. Fann M., et al. Histone acetylation is associated with differential gene expression in the rapid and robust memory CD8+ T cell response. Blood 108, 3363-3370 (2006
60. Araki Y., Fann M., Wersto R., & Weng N. P. Histone acetylation facilitates rapid and robust memory CD8 T cell response through differential expression of effector molecules (eomesodermin and its targets: perforin and granzyme B). J. Immunol. 180, 8102-8108 (2008
61. Araki Y., et al. Genome-wide analysis of histone methylation reveals chromatin state-based complex regulation of differential gene transcription and function of CD8 memory T cells. Immunity 30, 912-925 (2009
62. Northrop J. K., Wells A. D., & Shen H. Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T cells. J. Immunol. 181, 865-868 (2008
63. Manichanh C., Borruel N., Casellas F., & Guarner F. The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol. 9, 599-608 (2012
64. McGeachy M. J., et al. TGF-β and IL 6 drive the production of IL 17 and IL 10 by T cells and restrain TH 17 cell-mediated pathology. Nat. Immunol. 8, 1390-1397 (2007
65. Lee Y., et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13, 991-999 (2012
66. Lin Z., et al. Identification of disease-associated DNA methylation in B cells from Crohn?s disease and ulcerative colitis patients. Dig. Dis. Sci. 57, 3145-3153 (2012
67. Lleo A., et al. Immunoglobulin M levels inversely correlate with CD40 ligand promoter methylation in patients with primary biliary cirrhosis. Hepatology 55, 153-160 (2012
68. Liu C. C., et al. Global DNA methylation, DNMT1, and MBD2 in patients with rheumatoid arthritis. Immunol. Lett. 135, 96-99 (2011
69. Glossop J. R., et al. Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease-associated methylation changes that are distinct to individual T-and B lymphocyte populations. Epigenetics 9, 1228-1237 (2014
70. Altorok N., et al. Genome-wide DNA methylation patterns in naive CD4+ T cells from patients with primary Sjögren?s syndrome. Arthritis Rheumatol. 66, 731-739 (2014
71. Park G., Han J., Park S. G., Kim S., & Kim T. Y. DNA methylation analysis of CD4+ T cells in patients with psoriasis. Arch. Dermatol. Res. 306, 259-268 (2014
72. Richardson B., et al. Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 33, 1665-1673 (1990
73. Absher D. M., et al. Genome-wide DNA methylation analysis of systemic lupus erythematosus reveals persistent hypomethylation of interferon genes and compositional changes to CD4+ T cell populations. PLoS Genet. 9, e1003678 2013
74. Rakyan V. K., et al. Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet. 7, e1002300 2011
75. Mastronardi F. G., Noor A., Wood D. D., Paton T., & Moscarello M. A. Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. J. Neurosci. Res. 85, 2006-2016 (2007
76. Bos S. D., et al. Genome-wide DNA methylation profiles indicate CD8+ T cell hypermethylation in multiple sclerosis. PLoS ONE 10, e0117403 2015
77. Graves M. C., et al. Methylation differences at the HLA DRB1 locus in CD4+ T cells are associated with multiple sclerosis. Mult. Scler. 20, 1033-1041 (2014
78. Fukuhara T., et al. Hypermethylation of MST1 in IgG4 related autoimmune pancreatitis and rheumatoid arthritis. Biochem. Biophys. Res. Commun. 463, 968-974 (2015
79. Lian X., et al. DNA demethylation of CD40L in CD4+ T cells from women with systemic sclerosis: a possible explanation for female susceptibility. Arthritis Rheum. 64, 2338-2345 (2012
80. Lu Q., et al. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J. Immunol. 179, 6352-6358 (2007
81. Lu Q., Wu A., & Richardson B. C. Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. J. Immunol. 174, 6212-6219 (2005
82. Jiang H., et al. Demethylation of TNFSF7 contributes to CD70 overexpression in CD4+ T cells from patients with systemic sclerosis. Clin. Immunol. 143, 39-44 (2012
83. Wang Y. Y., et al. DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis. Br. J. Dermatol. 171, 39-47 (2014
84. Kennedy A., et al. A novel upstream enhancer of FOXP3, sensitive to methylation-induced silencing, exhibits dysregulated methylation in rheumatoid arthritis Treg cells. Eur. J. Immunol. 44, 2968-2978 (2014
85. Li Y., et al. Abnormal DNA methylation in CD4+ T cells from people with latent autoimmune diabetes in adults. Diabetes Res. Clin. Pract. 94, 242-248 (2011
86. Hori S., Nomura T., & Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057-1061 (2003
87. Cribbs A. P., et al. Treg cell function in rheumatoid arthritis is compromised by CTLA 4 promoter methylation resulting in a failure to activate the indoleamine 2,3 dioxygenase pathway. Arthritis Rheumatol. 66, 2344-2354 (2014
88. Wang Y., Fan P. S., & Kahaleh B. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum. 54, 2271-2279 (2006
89. Wang Y., & Kahaleh B. Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma. J. Cell. Mol. Med. 17, 1291-1299 (2013
90. Dees C., et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann. Rheum. Dis. 73, 1232-1239 (2014
91. Karouzakis E., Gay R. E., Michel B. A., Gay S., & Neidhart M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 60, 3613-3622 (2009
92. Nakano K., Whitaker J. W., Boyle D. L., Wang W., & Firestein G. S. DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis. 72, 110-117 (2013
93. Tak P. P., Zvaifler N. J., Green D. R., & Firestein G. S. Rheumatoid arthritis and p53: how oxidative stress might alter the course of inflammatory diseases. Immunol. Today 21, 78-82 (2000
94. Ai R., et al. DNA methylome signature in early rheumatoid arthritis synoviocytes compared with longstanding rheumatoid arthritis synoviocytes. Arthritis Rheumatol. 67,1978-1980 2015
95. Calabrese R., et al. TET2 gene expression and 5 hydroxymethylcytosine level in multiple sclerosis peripheral blood cells. Biochim. Biophys. Acta 1842, 1130-1136 (2014
96. Zhao M., et al. Increased 5 hydroxymethylcytosine in CD4+ T cells in systemic lupus erythematosus. J. Autoimmun. 69, 64-73 (2016
97. Hu N., et al. Abnormal histone modification patterns in lupus CD4+ T cells. J. Rheumatol. 35, 804-810 (2008
98. Zhang P., Su Y., Chen H., Zhao M., & Lu Q. Abnormal DNA methylation in skin lesions and PBMCs of patients with psoriasis vulgaris. J. Dermatol. Sci. 60, 40-42 (2010
99. Wang Y., et al. Aberrant histone modification in peripheral blood B cells from patients with systemic sclerosis. Clin. Immunol. 149, 46-54 (2013
100. Wada T. T., et al. Aberrant histone acetylation contributes to elevated interleukin 6 production in rheumatoid arthritis synovial fibroblasts. Biochem. Biophys. Res. Commun. 444, 682-686 (2014
101. Buckley C. D., Gilroy D. W., Serhan C. N., Stockinger B., & Tak P. P. The resolution of inflammation. Nat. Rev. Immunol. 13, 59-66 (2013
102. Sorm F., Piskala A., Cihak A., & Vesely J 5 Azacytidine, a new, highly effective cancerostatic. Experimentia 20 202-203 1964
103. Jones P. A., & Taylor S. M. Cellular differentiation, cytidine analogs and DNA methylation. Cell 20, 85-93 (1980
104. Lu L., & Randerath K. Mechanism of 5 azacytidine-induced transfer RNA cytosine-5 methyltransferase deficiency. Cancer Res. 40, 2701-2705 (1980
105. Lee T., & Karon M. Inhibition of protein synthesis in 5 azacytidine-treated HeLa cells. Biochem. Pharmacol. 25, 1737-1742 (1976
106. Almstedt M., et al. The DNA demethylating agent 5 aza 2′ deoxycytidine induces expression of NY ESO 1 and other cancer/testis antigens in myeloid leukemia cells. Leuk. Res. 34, 899-905 (2010
107. Lal G., et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J. Immunol. 182, 259-273 (2009
108. Wu C. J., et al. The DNA methylation inhibitor 5 azacytidine increases regulatory T cells and alleviates airway inflammation in ovalbumin-sensitized mice. Int. Arch. Allergy Immunol. 160, 356-364 (2013
109. Chan M. W. Y., et al. Low-dose 5 aza 2′ deoxycytidine pretreatment inhibits experimental autoimmune encephalomyelitis by induction of regulatory T cells. Mol. Med. 20, 248-256 (2014
110. Mangano K., et al. Hypomethylating agent 5 aza 2′ deoxycytidine (DAC) ameliorates multiple sclerosis in mouse models. J. Cell. Physiol. 229, 1918-1925 (2014
111. Zheng Q., et al. Induction of Foxp3 demethylation increases regulatory CD4+CD25+ T cells and prevents the occurrence of diabetes in mice. J. Mol. Med. 87, 1191-1205 (2009
112. Dunn J., et al. Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. J. Clin. Invest. 124, 3187-3199 (2014
113. Cao Q., et al. Inhibiting DNA methylation by 5 aza 2′ deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation. Endocrinology 155, 4925-4938 (2014
114. Guo H., et al. Inhibiting cardiac allograft rejection with interleukin 35 therapy combined with decitabine treatment in mice. Transpl. Immunol. 29, 99-104 (2013
115. Goodyear O. C., et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood 119, 3361-3369 (2012
116. Adair S., & Hogan K. Treatment of ovarian cancer cell lines with 5 aza 2′ deoxycytidine upregulates the expression of cancer-testis antigens and class I major histocompatibility complex-encoded molecules. Cancer Immunol. Immunother. 58, 589-601 (2009
117. Dubovsky J. A., et al. Treatment of chronic lymphocytic leukemia with a hypomethylating agent induces expression of NXF2, an immunogenic cancer testis antigen. Clin. Cancer Res. 15, 3406-3415 (2009
118. Wang L., et al. Decitabine enhances lymphocyte migration and function and synergizes with CTLA 4 blockade in a murine ovarian cancer model. Cancer Immunol. Res. 3, 1030-1041 (2015
119. Wang Y., et al. Hypomethylation and overexpression of ITGAL (CD11a) in CD4+ T cells in systemic sclerosis. Clin. Epigenet. 6, 25 (2014
120. Kadoch C., Copeland R. A., & Keilhack H. PRC2 and SWI/SNF chromatin remodeling complexes in health and disease. Biochemistry 55, 1600-1614 (2016
121. Su I., et al. Polycomb group protein Ezh2 controls actin polymerization and cell signaling. Cell 121, 425-436 (2005
122. He S., et al. The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T cell responses mediating graft-versus-host disease. Blood 122, 4119-4128 (2013
123. Zhang Y., et al. The polycomb repressive complex 2 governs life and death of peripheral T cells. Blood 124, 737-749 (2014
124. Yang X. P., et al. EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Sci. Rep. 5, 10643 (2015
125. Tough D. F., Lewis H. D., Rioja I., Lindon M. J., & Prinjha R. K. Epigenetic pathway targets for the treatment of disease: accelerating progress in the development of pharmacological tools: IUPHAR Review 11. Br. J. Pharmacol. 171, 4981-5010 (2014
126. Fang T. C., et al. Histone H3 lysine 9 di methylation as an epigenetic signature of the interferon response. J. Exp. Med. 209, 661-669 (2012
127. Gregoretti I., Lee Y. M., & Goodson H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 338, 17-31 (2004
128. Bantscheff M., et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat. Biotechnol. 29, 255-265 (2011
129. Khan O., & La Thangue N. B. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol. Cell Biol. 90, 85-94 (2012
130. Lobera M., et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat. Chem. Biol. 9, 319-325 (2013
131. Cantley M. D., & Haynes D. R. Epigenetic regulation of inflammation: progressing from broad acting histone deacetylase (HDAC) inhibitors to targeting specific HDACs. Inflammopharmacology 21, 301-307 (2013
132. Hu E., et al. Identification of novel isoform-selective inhibitors within class i histone deacetylases. J. Pharmacol. Exp. Ther. 307, 720-728 (2003
133. Jochems J., et al. Antidepressant-like properties of novel HDAC6 selective inhibitors with improved brain bioavailability. Neuropsychopharmacology 39, 389-400 (2014
134. Schlimme S., et al. Carbamate prodrug concept for hydroxamate HDAC inhibitors. Chem. Med. Chem 6, 1193-1198 (2011
135. Greer C. B., et al. Histone deacetylases positively regulate transcription through the elongation machinery. Cell Rep. 13, 1444-1455 (2015
136. Grabiec A. M., Korchynskyi O., Tak P. P., & Reedquist K. A. Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL 6 production by accelerating mRNA decay. Ann. Rheum. Dis. 71, 424-431 (2012
137. Leoni F., et al. The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc. Natl Acad. Sci. USA 99, 2995-3000 (2002
138. Leoni F., et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol. Med. 11, 1-15 (2005
139. Li S., et al. Specific inhibition of histone deacetylase 8 reduces gene expression and production of proinflammatory cytokines in vitro and in vivo. J. Biol. Chem. 290, 2368-2378 (2015
140. Mishra N., Reilly C. M., Brown D. R., Ruiz P., & Gilkeson G. S. Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J. Clin. Invest. 111, 539-552 (2003
141. Li Y., et al. Inhibition of histone deacetylase 6 improves long-term survival in a lethal septic model. J. Trauma Acute Care Surg. 78, 378-385 (2015
142. Wu C., Li A., Leng Y., Li Y., & Kang J. Histone deacetylase inhibition by sodium valproate regulates polarization of macrophage subsets. DNA Cell Biol. 31, 592-599 (2011
143. Wang B., Morinobu A., Horiuchi M., Liu J., & Kumagai S. Butyrate inhibits functional differentiation of human monocyte-derived dendritic cells. Cell. Immunol. 253, 54-58 (2008
144. Frikeche J., et al. Impact of valproic acid on dendritic cells function. Immunobiology 217, 704-710 (2012
145. Brogdon J., et al. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector function. Blood 109, 1123-1130 (2007
146. Bosisio D., et al. Blocking TH17 polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo. J. Leukocyte Biol. 84, 1540-1548 (2008
147. Su R. C., Becker A. B., Kozyrskyj A. L., & HayGlass K. T. Epigenetic regulation of established human type 1 versus type 2 cytokine responses. J. Allergy Clin. Immunol. 121, 57-63 (2008
148. Arbez J., Lamarth?e B., Gaugler B., & Saas P. Histone deacetylase inhibitor valproic acid affects plasmacytoid dendritic cells phenotype and function. Immunobiology 219, 637-643 (2014
149. Tao R., et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat. Med. 13, 1299-1307 (2007
150. Waibel M., et al. Manipulation of B cell responses with histone deacetylase inhibitors. Nat. Commun. 6, 6838 (2015
151. Chung Y., Lee M., Wang A., & Yao L. A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis. Mol. Ther. 8, 707-717 (2003
152. Choi J. H., et al. Trichostatin A attenuates airway inflammation in mouse asthma model. Clin. Exp. Allergy 35, 89-96 (2005
153. Hartman H., Wetterholm E., Thorlacius H., & Regn?r S. Histone deacetylase regulates trypsin activation, inflammation, and tissue damage in acute pancreatitis in mice. Dig. Dis. Sci. 60, 1284-1289 (2015
154. Marumo T., et al. Histone deacetylase modulates the proinflammatory and-fibrotic changes in tubulointerstitial injury. Am. J. Physiol. Renal Physiol. 298, F133-F141 2009
155. Zhao T. C., Du J., Zhuang S., Liu P., & Zhang L. X. HDAC inhibition elicits myocardial protective effect through modulation of MKK3/Akt 1. PLoS ONE 8, e65474 2013
156. Zhang L., Jin S., Wang C., Jiang R., & Wan J. Histone deacetylase inhibitors attenuate acute lung injury during cecal ligation and puncture-induced polymicrobial sepsis. World J. Surg. 34, 1676-1683 (2010
157. Camelo S., et al. Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J. Neuroimmunol. 164, 10-21 (2005
158. Glauben R., Sonnenberg E., Wetzel M., Mascagni P., & Siegmund B. Histone deacetylase inhibitors modulate interleukin 6 dependent CD4+ T cell polarization in vitro and in vivo. J. Biol. Chem. 289, 6142-6151 (2014
159. Regna N. L., et al. Class I and II histone deacetylase inhibition by ITF2357 reduces SLE pathogenesis in vivo. Clin. Immunol. 151, 29-42 (2014
160. Reddy P., et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc. Natl Acad. Sci. USA 101, 3921-3926 (2004
161. Joosten L. A., Leoni F., Meghji S., & Mascagni P. Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. Mol. Med. 17, 391-396 (2011
162. Lewis E. C., et al. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro. Mol. Med. 17, 369-377 (2011
163. Glauben R., et al. Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J. Immunol. 176, 5015-5022 (2006
164. Nishida K., et al. Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21WAF1/Cip1 expression. Arthritis Rheum. 50, 3365-3376 (2004
165. Hsieh I. N., et al. Preclinical anti-arthritic study and pharmacokinetic properties of a potent histone deacetylase inhibitor MPT0G009. Cell Death Dis. 5, e1166 2014
166. Cantley M. D., et al. Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in arthritis. Rheumatology 54, 1713-1723 (2015
167. Nakamura T., et al. Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN β production. J. Immunol. 175, 5809-5816 (2005
168. Schroeder T. M., & Westendorf J. J. Histone deacetylase inhibitors promote osteoblast maturation. J. Bone Miner. Res. 20, 2254-2263 (2005
169. Grabiec A. M., et al. Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. J. Immunol. 184, 2718-2728 (2010
170. J?ngel A., et al. Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Ann. Rheum. Dis. 65, 910-912 (2006
171. Gillespie J., et al. Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin 6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum. 64, 418-422 (2012
172. Furlan A., et al. Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Mol. Med. 17, 353-362 (2011
173. Choi S. W., et al. Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans. Blood 125, 815-819 (2015
174. Bodar E. J., Simon A., & van der Meer J. W. Effects of the histone deacetylase inhibitor ITF2357 in autoinflammatory syndromes. Mol. Med. 17, 363-368 (2011
175. Vojinovic J., et al. Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 63, 1452-1458 (2011
176. Kong S., Yeung P., & Fang D. The class III histone deacetylase sirtuin 1 in immune suppression and its therapeutic potential in rheumatoid arthritis. J. Genet. Genomics 40, 347-354 (2013
177. Gao X., Xu Y. X., Janakiraman N., Chapman R. A., & Gautam S. C. Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production. Biochem. Pharmacol. 62, 1299-1308 (2001
178. Zou T., et al. Resveratrol inhibits CD4+ T cell activation by enhancing the expression and activity of Sirt1. PLoS ONE 8, e75139 2013
179. Sharma S., Chopra K., Kulkarni S. K., & Agrewala J. N. Resveratrol and curcumin suppress immune response through CD28/CTLA 4 and CD80 co stimulatory pathway. Clin. Exp. Immunol. 147, 155-163 (2007
180. Xuzhu G., et al. Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B cell function. Ann. Rheum. Dis. 71, 129-135 (2012
181. Shindler K. S., et al. Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J. Neuroophthalmol. 30, 328-339 (2010
182. Dittenhafer-Reed K. E., Feldman J. L., & Denu J. M. Catalysis and mechanistic insights on sirtuin activation. Chem. Bio. Chem 12, 281-289 (2011
183. Hubbard B. P., et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339, 1216-1219 (2013
184. Jia Y., et al. SIRT1 is a regulator in high glucose-induced inflammatory response in RAW264.7 cells. PLoS ONE 10, e0120849 2015
185. Ichikawa T., et al. Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma. Respirology 18, 332-339 (2013
186. Hoffmann E., et al. Pharmacokinetics and tolerability of SRT2104, a first in class small molecule activator of SIRT1, after single and repeated oral administration in man. Br. J. Clin. Pharmacol. 75, 186-196 (2013
187. Libri V., et al A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers PLoS ONE 7, e51395 (2012
188. Filippakopoulos P., & Knapp S. The bromodomain interaction module. FEBS Lett. 586, 2692-2704 (2012
189. Chung C. W. Small molecule bromodomain inhibitors: extending the druggable genome. Prog. Med. Chem. 51, 1-55 (2012
190. Barda S., et al. Expression of BET genes in testis of men with different spermatogenic impairments. Fertil. Steril. 97, 46-52 (2012
191. Jang M. K., et al. The bromodomain protein Brd4 is a positive regulatory component of P TEFb and stimulates RNA polymerase II dependent transcription. Mol. Cell 19, 523-534 (2005
192. Anand P., et al. BET bromodomains mediate transcriptional pause release in heart failure. Cell 154, 569-582 (2013
193. Zhang W., et al. Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation inhuman CD4+ T cells. J. Biol. Chem. 287, 43137-43155 (2012
194. Lamonica J. M., et al. Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes. Proc. Natl Acad. Sci. USA 108, E159-E168 2011
195. Huang B., Yang X. D., Zhou M. M., Ozato K., & Chen L. F. Brd4 coactivates transcriptional activation of NF κB via specific binding to acetylated RelA. Mol. Cell. Biol. 29, 1375-1387 (2009
196. Shi J., et al. Disrupting the interaction of BRD4 with diacetylated twist suppresses tumorigenesis in basal-like breast cancer. Cancer Cell 25, 210-225 (2014
197. Nicodeme E., et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119-1123 (2010
198. Filippakopoulos P., et al. Selective inhibition of BET bromodomains. Nature 468, 1067-1073 (2010
199. Noel J. K., et al. Development of the BET bromodomain inhibitor OTX015. Mol. Cancer Ther. 12, C244 2013
200. Mirguet O., et al. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J. Med. Chem. 56, 7501-7515 (2013
201. Zhang G., et al. Down-regulation of NF κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J. Biol. Chem. 287, 28840-28851 (2012
202. Fish P. V., et al. Identification of a chemical probe for bromo and extra C terminal bromodomain inhibition through optimization of a fragment-derived hit. J. Med. Chem. 55, 9831-9837 (2012
203. Khmelnitsky Y. L., et al. In vitro biosynthesis, isolation, and identification of predominant metabolites of 2-(4-(2 hydroxyethoxy)-3,5 dimethylphenyl)-5,7 dimethoxyquinazolin 4(3H)-one (RVX 208). Eur. J. Med. Chem. 64, 121-128 (2013
204. Ran X., et al. Structure-based design of γ carboline analogues as potent and specific BET bromodomain inhibitors. J. Med. Chem. 58, 4927-4939 (2015
205. Dittmann A., et al. The commonly used PI3 kinase probe LY294002 is an inhibitor of BET bromodomains. ACS Chem. Biol. 9, 495-502 (2014
206. Gacias M., et al. Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem. Biol. 21, 841-854 (2014
207. Belkina A. C., Nikolajczyk B. S., & Denis G. V. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. J. Immunol. 190, 3670-3678 (2013
208. Barrett E., Brothers S., Wahlestedt C., & Beurel E. I-BET151 selectively regulates IL 6 production. Biochim. Biophys. Acta 1842, 1549-1555 (2014
209. Wienerroither S., et al. Regulation of NO synthesis, local inflammation, and innate immunity to pathogens by BET family proteins. Mol. Cell. Biol. 34, 415-427 (2014
210. Meng S., et al. BET inhibitor JQ1 blocks inflammation and bone destruction. J. Dental Res. 93, 657-662 (2014
211. Qiao Y., et al. Synergistic activation of inflammatory cytokine genes by interferon-γ induced chromatin remodeling and Toll-like receptor signaling. Immunity 39, 454-469 (2013
212. Chan C. H., et al. BET bromodomain inhibition suppresses transcriptional responses to cytokine-Jak-STAT signaling in a gene-specific manner in human monocytes. Eur. J. Immunol. 45, 287-297 (2015
213. Toniolo P. A., et al. Inhibiting STAT5 by the BET bromodomain inhibitor JQ1 disrupts human dendritic cell maturation. J. Immunol. 194, 3180-3190 (2015
214. Bandukwala H. S., et al. Selective inhibition of CD4+ T cell cytokine production and autoimmunity by BET protein and c Myc inhibitors. Proc. Natl Acad. Sci. USA 109, 14532-14537 (2012
215. Mele D. A., et al. BET bromodomain inhibition suppresses TH17 mediated pathology. J. Exp. Med. 210, 2181-2190 (2013
216. Belkina A. C., Blanton W. P., Nikolajczyk B. S., & Denis G. V. The double bromodomain protein Brd2 promotes B cell expansion and mitogenesis. J. Leukocyte Biol. 95, 451-460 (2014
217. Stanlie A., Yousif A., Akiyama H., Honjo T., & Begum N. Chromatin reader Brd4 functions in Ig class switching as a repair complex adaptor of nonhomologous end-joining. Mol. Cell 55, 97-110 (2014
218. Park-Min K. H., et al. Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation. Nat. Commun. 5, 5418 (2014
219. Klein K., et al. The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis. 75, 422-429 (2016
220. Perry M. M., Durham A. L., Austin P. J., Adcock I. M., & Chung K. F. BET bromodomains regulate transforming growth factor-β induced proliferation and cytokine release in asthmatic airway smooth muscle. J. Biol. Chem. 290, 9111-9121 (2015
221. Clifford R. L., et al. CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L962-L972 2015
222. Khan Y. M., Kirkham P., Barnes P. J., & Adcock I. M. Brd4 is essential for il 1β induced inflammation in human airway epithelial cells. PLoS ONE 9, e95051 2014
223. Brown J. D., et al. NF κB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol. Cell 56, 1-13 (2014
224. Michaeloudes C., et al. Bromodomain and extraterminal proteins suppress NF E2 related factor 2 mediated antioxidant gene expression. J. Immunol. 192, 4913-4920 (2014
225. Jahagirdar R., et al A novel BET bromodomain inhibitor, RVX 208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice. Atherosclerosis 236, 91-100 2014
226. Nadeem A., et al. Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL 17A pathway modulation. Pharmacol. Res. 99, 248-257 (2015
227. Fu W., et al. Epigenetic modulation of type 1 diabetes via a dual effect on pancreatic macrophages and β cells. eLife 3, e04631 2014
228. Zhang Q. G., Qian J., & Zhu Y. C. Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis. Immunol. Lett. 166, 103-108 (2015
229. Prinjha R. K., Witherington J., & Lee K. Place your BETs: the therapeutic potential of bromodomains. Trends Pharmacol. Sci. 33, 146-153 (2012
230. Schulz D., et al. Bromodomain proteins contribute to maintenance of bloodstream form stage identity in the African trypanosome. PLoS Biol. 13, e1002316 2015
231. Kruidenier L., et al A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488 404-408 2012