The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD)

Journal of Biological Chemistry

Volumn 292, Issue 2, 2017, Pages 706-722

  Sarmento, Olga F ^a   Svingen, Phyllis A ^a   Xiong, Yuning ^a   Sun, Zhifu ^a   Bamidele, Adebowale O ^a   Mathison, Angela J ^a   Smyrk, Thomas C ^a   Nair, Asha A ^a   Gonzalez, Michelle M ^a   Sagstetter, Mary R ^a   Baheti, Saurabh ^a   McGovern, Dermot P B ^b   Friton, Jessica J ^a   Papadakis, Konstantinos A ^a   Gautam, Goel ^c,d   Xavier, Ramnik J ^c,d   Urrutia, Raul A ^a   Faubion, William A ^a  

^a MAYO CLINIC   (United States)

^b CEDARS SINAI MEDICAL CENTER   (United States)

^c MASSACHUSETTS GENERAL HOSPITAL   (United States)

^d BROAD INSTITUTE OF MIT AND HARVARD   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOLOGY; DISEASES; MAMMALS; TRANSCRIPTION;

CELLULAR FUNCTION; CROHN'S DISEASE; HISTONE METHYLTRANSFERASE; INFLAMMATORY BOWEL DISEASE; INTESTINAL INFLAMMATION; PRO-INFLAMMATORY CYTOKINES; RNA SEQUENCING; SELF TOLERANCE;

T-CELLS;

CYTOKINE; TRANSCRIPTION FACTOR EZH2; TRANSCRIPTION FACTOR FOXP3; EZH2 PROTEIN, HUMAN; EZH2 PROTEIN, MOUSE; FORKHEAD TRANSCRIPTION FACTOR; FOXP3 PROTEIN, HUMAN; FOXP3 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CD4+ T LYMPHOCYTE; CELL FUNCTION; CONTROLLED STUDY; CROHN DISEASE; CYTOKINE RELEASE; EFFECTOR CELL; ENTERITIS; GENE CONTROL; GENE DISRUPTION; GENE REGULATORY NETWORK; HUMAN; HUMAN TISSUE; IMMUNOREACTIVITY; IN VITRO STUDY; INFLAMMATORY BOWEL DISEASE; LYMPHOCYTE TRANSFORMATION; MALE; MORTALITY; MOUSE; MURINE MODEL; NONHUMAN; PHENOTYPE; PROTEIN EXPRESSION; PROTEIN FUNCTION; REGULATORY T LYMPHOCYTE; RNA SEQUENCE; TH1 CELL; TH17 CELL; ANIMAL; GENETICS; IMMUNOLOGY; PATHOLOGY; TRANSGENIC MOUSE;

ANIMALS; CROHN DISEASE; CYTOKINES; ENHANCER OF ZESTE HOMOLOG 2 PROTEIN; FORKHEAD TRANSCRIPTION FACTORS; GENE REGULATORY NETWORKS; HUMANS; MICE; MICE, TRANSGENIC; T-LYMPHOCYTES, REGULATORY; TH17 CELLS;

EID: 85009804809     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M116.749663     Document Type: Article

References (60)

1. Jostins, L., Ripke, S., Weersma, R. K., Duerr, R. H., McGovern, D. P., Hui, K. Y., Lee, J. C., Schumm, L. P., Sharma, Y., Anderson, C. A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., et al. (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124
2. Zhu, J., Yamane, H., and Paul, W. E. (2010) Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445-489
3. Luo, C. T., Liao, W., Dadi, S., Toure, A., and Li, M. O. (2016) Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity. Nature 529, 532-536
4. Yang, X. P., Jiang, K., Hirahara, K., Vahedi, G., Afzali, B., Sciume, G., Bonelli, M., Sun, H. W., Jankovic, D., Kanno, Y., Sartorelli, V., O'Shea, J. J., and Laurence, A. (2015) EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Sci. Rep. 5, 10643
5. Lal, G., and Bromberg, J. S. (2009) Epigenetic mechanisms of regulation of Foxp3 expression. Blood 114, 3727-3735
6. Michels, A. W., and Gottlieb, P. A. (2010) Autoimmune polyglandular syndromes. Nat. Rev. Endocrinol. 6, 270-277
7. Ramsdell, F., and Ziegler, S. F. (2014) FOXP3 and scurfy: how it all began. Nat. Rev. Immunol. 14, 343-349
8. O'Meara, M. M., and Simon, J. A. (2012) Inner workings and regulatory inputs that control Polycomb repressive complex 2. Chromosoma 121, 221-234
9. Mandal, M., Powers, S. E., Maienschein-Cline, M., Bartom, E. T., Hamel, K. M., Kee, B. L., Dinner, A. R., and Clark, M. R. (2011) Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2. Nat. Immunol. 12, 1212-1220
10. Jacob, E., Hod-Dvorai, R., Schif-Zuck, S., and Avni, O. (2008) Unconventional association of the polycomb group proteins with cytokine genes in differentiated T helper cells. J. Biol. Chem. 283, 13471-13481
11. Tumes, D. J., Onodera, A., Suzuki, A., Shinoda, K., Endo, Y., Iwamura, C., Hosokawa, H., Koseki, H., Tokoyoda, K., Suzuki, Y., Motohashi, S., and Nakayama, T. (2013) The polycomb protein Ezh2 regulates differentiation and plasticity of CD4(+) T helper type 1 and type 2 cells. Immunity 39, 819-832
12. Xiong, Y., Khanna, S., Grzenda, A. L., Sarmento, O. F., Svingen, P. A., Lomberk, G. A., Urrutia, R. A., and Faubion, W. A., Jr. (2012) Polycomb antagonizes p300/CREB-binding protein-associated factor to silence FOXP3 in a Kruppel-like factor-dependent manner. J. Biol. Chem. 287, 34372-34385
13. Arvey, A., van der Veeken, J., Samstein, R. M., Feng, Y., Stamatoyannopoulos, J. A., and Rudensky, A. Y. (2014) Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat. Immunol. 15, 580-587
14. DuPage, M., Chopra, G., Quiros, J., Rosenthal, W. L., Morar, M. M., Holohan, D., Zhang, R., Turka, L., Marson, A., and Bluestone, J. A. (2015) The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity 42, 227-238
15. Godfrey, V. L., Wilkinson, J. E., and Russell, L. B. (1991) X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am. J. Pathol. 138, 1379-1387
16. Tone, Y., Kidani, Y., Ogawa, C., Yamamoto, K., Tsuda, M., Peter, C., Waldmann, H., and Tone, M. (2014) Gene expression in the Gitr locus is regulated by NF-κB and Foxp3 through an enhancer. J. Immunol. 192, 3915-3924
17. Kornete, M., Sgouroudis, E., and Piccirillo, C. A. (2012) ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice. J. Immunol. 188, 1064-1074
18. Hovhannisyan, Z., Treatman, J., Littman, D. R., and Mayer, L. (2011) Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology 140, 957-965
19. Ueno, A., Jijon, H., Chan, R., Ford, K., Hirota, C., Kaplan, G. G., Beck, P. L., Iacucci, M., Fort Gasia, M., Barkema, H. W., Panaccione, R., and Ghosh, S. (2013) Increased prevalence of circulating novel IL-17 secreting Foxp3 expressing CD4+ T cells and defective suppressive function of circulating Foxp3+ regulatory cells support plasticity between Th17 and regulatoryT cells in inflammatory bowel disease patients. Inflamm. Bowel Dis. 19, 2522-2534
20. Shi, L., Song, L., Fitzgerald, M., Maurer, K., Bagashev, A., and Sullivan, K. E. (2014) Noncoding RNAs and LRRFIP1 regulate TNF expression. J. Immunol. 192, 3057-3067
21. Bantug, G. R., and Hess, C. (2016) Glycolysis and EZH2 boost T cell weaponry against tumors. Nat. Immunol. 17, 41-42
22. Saeidi, K. (2016) Myeloproliferative neoplasms: current molecular biology and genetics. Crit. Rev. Oncol. Hematol. 98, 375-389
23. Tan, J., Yang, X., Zhuang, L., Jiang, X., Chen, W., Lee, P. L., Karuturi, R. K., Tan, P. B., Liu, E. T., and Yu, Q. (2007) Pharmacologic disruption of Polycomb- repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 21, 1050-1063
24. Varambally, S., Cao, Q., Mani, R. S., Shankar, S., Wang, X., Ateeq, B., Laxman, B., Cao, X., Jing, X., Ramnarayanan, K., Brenner, J. C., Yu, J., Kim, J. H., Han, B., Tan, P., et al. (2008) Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 1695-1699
25. Miranda, T. B., Cortez, C. C., Yoo, C. B., Liang, G., Abe, M., Kelly, T. K., Marquez, V. E., and Jones, P. A. (2009) DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol. Cancer Ther. 8, 1579-1588
26. Perse, M., and Cerar, A. (2012) Dextran sodium sulphate colitis mouse model: traps and tricks. J. Biomed. Biotechnol. 2012, 718617
27. Schubert, L. A., Jeffery, E., Zhang, Y., Ramsdell, F., and Ziegler, S. F. (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J. Biol. Chem. 276, 37672-37679
28. Fulton, D. L., Sundararajan, S., Badis, G., Hughes, T. R., Wasserman, W. W., Roach, J. C., and Sladek, R. (2009) TFCat: the curated catalog of mouse and human transcription factors. Genome Biol. 10, R29
29. Fletcher, M. N., Castro, M. A., Wang, X., de Santiago, I., O'Reilly, M., Chin, S. F., Rueda, O. M., Caldas, C., Ponder, B. A., Markowetz, F., and Meyer, K. B. (2013) Master regulators of FGFR2 signalling and breast cancer risk. Nat. Commun. 4, 2464
30. Carro, M. S., Lim, W. K., Alvarez, M. J., Bollo, R. J., Zhao, X., Snyder, E. Y., Sulman, E. P., Anne, S. L., Doetsch, F., Colman, H., Lasorella, A., Aldape, K., Califano, A., and Iavarone, A. (2010) The transcriptional network for mesenchymal transformation of brain tumours. Nature 463, 318-325
31. Gavin, M. A., Rasmussen, J. P., Fontenot, J. D., Vasta, V., Manganiello, V. C., Beavo, J. A., and Rudensky, A. Y. (2007) Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771-775
32. Zhang, Y., Kinkel, S., Maksimovic, J., Bandala-Sanchez, E., Tanzer, M. C., Naselli, G., Zhang, J. G., Zhan, Y., Lew, A. M., Silke, J., Oshlack, A., Blewitt, M. E., and Harrison, L. C. (2014) The polycomb repressive complex 2 governs life and death of peripheral T cells. Blood 124, 737-749
33. Zhang, H., Nestor, C. E., Zhao, S., Lentini, A., Bohle, B., Benson, M., and Wang, H. (2013) Profiling of human CD4+ T-cell subsets identifies the TH2-specific noncoding RNA GATA3-AS1. J. Allergy Clin. Immunol. 132, 1005-1008
34. Feinberg, A. P., Koldobskiy, M. A., and Göndör, A. (2016) Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 17, 284-299
35. Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., and Littman, D. R. (2006) The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121-1133
36. Martinez, G. J., Zhang, Z., Chung, Y., Reynolds, J. M., Lin, X., Jetten, A. M., Feng, X. H., and Dong, C. (2009) Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation. J. Biol. Chem. 284, 35283-35286
37. Voo, K. S., Wang, Y. H., Santori, F. R., Boggiano, C., Wang, Y. H., Arima, K., Bover, L., Hanabuchi, S., Khalili, J., Marinova, E., Zheng, B., Littman, D. R., and Liu, Y. J. (2009) Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc. Natl. Acad. Sci. U.S.A. 106, 4793-4798
38. Blatner, N. R., Mulcahy, M. F., Dennis, K. L., Scholtens, D., Bentrem, D. J., Phillips, J. D., Ham, S., Sandall, B. P., Khan, M. W., Mahvi, D. M., Halverson, A. L., Stryker, S. J., Boller, A. M., Singal, A., Sneed, R. K., et al. (2012) Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer. Sci. Transl. Med. 4, 164ra159
39. Tartar, D. M., VanMorlan, A. M., Wan, X., Guloglu, F. B., Jain, R., Haymaker, C. L., Ellis, J. S., Hoeman, C. M., Cascio, J. A., Dhakal, M., Oukka, M., and Zaghouani, H. (2010) FoxP3+ RORt+ T helper intermediates display suppressive function against autoimmune diabetes. J. Immunol. 184, 3377-3385
40. Wu, S. C., and Zhang, Y. (2011) Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of enhancer of zeste 2 (Ezh2) regulates its stability. J. Biol. Chem. 286, 28511-28519
41. Wan, J., Zhan, J., Li, S., Ma, J., Xu, W., Liu, C., Xue, X., Xie, Y., Fang, W., Chin, Y. E., and Zhang, H. (2015) PCAF-primed EZH2 acetylation regulates its stability and promotes lung adenocarcinoma progression. Nucleic Acids Res. 43, 3591-3604
42. Chu, C. S., Lo, P. W., Yeh, Y. H., Hsu, P. H., Peng, S. H., Teng, Y. C., Kang, M. L., Wong, C. H., and Juan, L. J. (2014) O-GlcNAcylation regulates EZH2 protein stability and function. Proc. Natl. Acad. Sci. U.S.A. 111, 1355-1360
43. Sahasrabuddhe, A. A., Chen, X., Chung, F., Velusamy, T., Lim, M. S., and Elenitoba-Johnson, K. S. (2015) Oncogenic Y641 mutations in EZH2 prevent Jak2/beta-TrCP-mediated degradation. Oncogene 34, 445-454
44. Harms, P. W., Hristov, A., Kim, D. S., Quist, T. A., Quist, M. J., Siddiqui, J., Carskadon, S., Mehra, R., Fullen, D. R., Johnson, T. M., Chinnaiyan, A. M., and Palanisamy, N. (2014) Activating mutations of the oncogene EZH2 in cutaneous melanoma revealed by next generation sequencing. Hum. Pathol. Case Rep. 1, 21-28
45. Yap, D. B., Chu, J., Berg, T., Schapira, M., Cheng, S. W., Moradian, A., Morin, R. D., Mungall, A. J., Meissner, B., Boyle, M., Marquez, V. E., Marra, M. A., Gascoyne, R. D., Humphries, R. K., Arrowsmith, C. H., et al. (2011) Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451-2459
46. Wigle, T. J., Knutson, S. K., Jin, L., Kuntz, K. W., Pollock, R. M., Richon, V. M., Copeland, R. A., and Scott, M. P. (2011) The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states. FEBS Lett. 585, 3011-3014
47. Kim, E., Kim, M., Woo, D. H., Shin, Y., Shin, J., Chang, N., Oh, Y. T., Kim, H., Rheey, J., Nakano, I., Lee, C., Joo, K. M., Rich, J. N., Nam, D. H., and Lee, J. (2013) Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23, 839-852
48. Chen, B., Liu, J., Chang, Q., Beezhold, K., Lu, Y., and Chen, F. (2013) JNK and STAT3 signaling pathways converge on Akt-mediated phosphorylation of EZH2 in bronchial epithelial cells induced by arsenic. Cell Cycle 12, 112-121
49. Xu, B., Konze, K. D., Jin, J., and Wang, G. G. (2015) Targeting EZH2 and PRC2 dependence as novel anticancer therapy. Exp. Hematol. 43, 698-712
50. Su, I. H., Dobenecker, M. W., Dickinson, E., Oser, M., Basavaraj, A., Marqueron, R., Viale, A., Reinberg, D., Wülfing, C., and Tarakhovsky, A. (2005) Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell 121, 425-436
51. Barzaghi, F., Passerini, L., and Bacchetta, R. (2012) Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front. Immunol. 3, 211
52. Rahman, M. K., Midtling, E. H., Svingen, P. A., Xiong, Y., Bell, M. P., Tung, J., Smyrk, T., Egan, L. J., and Faubion, W. A., Jr. (2010) The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell survival. J. Immunol. 184, 7247-7256
53. Faubion, W. A., De Jong, Y. P., Molina, A. A., Ji, H., Clarke, K., Wang, B., Mizoguchi, E., Simpson, S. J., Bhan, A. K., and Terhorst, C. (2004) Colitis is associated with thymic destruction attenuating CD4+ 25+ regulatory T cells in the periphery. Gastroenterology 126, 1759-1770
54. Duijvestein, M., Wildenberg, M. E., Welling, M. M., Hennink, S., Molendijk, I., van Zuylen, V. L., Bosse, T., Vos, A. C., de Jonge-Muller, E. S., Roelofs, H., van der Weerd, L., Verspaget, H. W., Fibbe, W. E., te Velde, A. A., van den Brink, G. R., and Hommes, D. W. (2011) Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells 29, 1549-1558
55. Langmead, B., Trapnell, C., Pop, M., and Salzberg, S. L. (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25
56. Trapnell, C., Pachter, L., and Salzberg, S. L. (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105-1111
57. Anders, S., Pyl, P. T., and Huber, W. (2015) HTSeq: a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166-169
58. Robinson, M. D., McCarthy, D. J., and Smyth, G. K. (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139-140
59. Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L., and Wold, B. (2008) Mapping and quantifying mammalian transcriptomes by RNASeq. Nat. Methods 5, 621-628
60. Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., and Mesirov, J. P. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U.S.A. 102, 15545-15550