Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells

eLife

Volumn 3, Issue November, 2014, Pages 1-20

  Fu, Wenxian ^a,e   Farache, Julia ^a   Clardy, Susan M ^b   Hattori, Kimie ^a   Mander, Palwinder ^c   Lee, Kevin ^c,f   Rioja, Inmaculada ^c   Weissleder, Ralph ^b   Prinjha, Rab K ^c   Benoist, Christophe ^a,d   Mathis, Diane ^a,d  

^a HARVARD MEDICAL SCHOOL   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

^c GLAXOSMITHKLINE   (United Kingdom)

^d BRIGHAM AND WOMEN S HOSPITAL   (United States)

^e UNIVERSITY OF CALIFORNIA   (United States)

^f PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCOSE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LIVER X RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; 7 (3,5 DIMETHYL 4 ISOXAZOLYL) 1,3 DIHYDRO 8 METHOXY 1 [1 (2 PYRIDINYL)ETHYL] 2H IMIDAZO[4,5 C]QUINOLIN 2 ONE; FUSED HETEROCYCLIC RINGS;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CD4+ T LYMPHOCYTE; CELL PROLIFERATION; CELL REGENERATION; CONTROLLED STUDY; CYTOFLUOROMETRY; DOWN REGULATION; EPIGENETICS; FLOW CYTOMETRY; HISTOLOGY; IMMUNOHISTOCHEMISTRY; INSULIN DEPENDENT DIABETES MELLITUS; MACROPHAGE; MICROARRAY ANALYSIS; MICROSCOPY; MOUSE; NONHUMAN; PANCREAS ISLET BETA CELL; PROTEIN EXPRESSION; TRANSCRIPTOMICS; UPREGULATION; ANIMAL; CYTOLOGY; DIABETES MELLITUS, TYPE 1; DRUG EFFECTS; FEMALE; GENETIC EPIGENESIS; GENETIC TRANSCRIPTION; GENETICS; IMMUNOLOGY; INFLAMMATION; METABOLISM; MONOCYTE; NONOBESE DIABETIC MOUSE; PATHOLOGY; PHENOTYPE; REGENERATION; SIGNAL TRANSDUCTION;

MUS;

ANIMALS; CD4-POSITIVE T-LYMPHOCYTES; DIABETES MELLITUS, TYPE 1; EPIGENESIS, GENETIC; FEMALE; HETEROCYCLIC COMPOUNDS WITH 4 OR MORE RINGS; INFLAMMATION; INSULIN-SECRETING CELLS; MACROPHAGES; MICE, INBRED NOD; MONOCYTES; NF-KAPPA B; PHENOTYPE; REGENERATION; SIGNAL TRANSDUCTION; TRANSCRIPTION, GENETIC;

EID: 84923029507     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.04631     Document Type: Article

References (86)

1. Anand P, Brown JD, Lin CY, Qi J, Zhang R, Artero PC, Alaiti MA, Bullard J, Alazem K, Margulies KB, Cappola TP, Lemieux M, Plutzky J, Bradner JE, Haldar SM. 2013. BET bromodomains mediate transcriptional pause release in heart failure. Cell 154:569-582. doi: 10.1016/j.cell.2013.07.013.
2. Anderson MS, Bluestone JA. 2005. The NOD mouse: a model of immune dysregulation. Annual Review of Immunology 23:447-485. doi: 10.1146/annurev.immunol.23.021704.115643.
3. Banaei-Bouchareb L, Gouon-Evans V, Samara-Boustani D, Castellotti MC, Czernichow P, Pollard JW, Polak M. 2004. Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. Journal of Leukocyte Biology 76:359-367. doi: 10.1189/jlb.1103591.
4. Bandukwala HS, Gagnon J, Togher S, Greenbaum JA, Lamperti ED, Parr NJ, Molesworth AM, Smithers N, Lee K, Witherington J, Tough DF, Prinjha RK, Peters B, Rao A. 2012. Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proceedings of the National Academy of Sciences of USA 109:14532-14537. doi: 10.1073/pnas.1212264109.
5. Belkina AC, Nikolajczyk BS, Denis GV. 2013. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. The Journal of Immunology 190:3670-3678. doi: 10.4049/jimmunol.1202838.
6. Bensinger SJ, Tontonoz P. 2008. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454:470-477. doi: 10.1038/nature07202.
7. Bluestone JA, Herold K, Eisenbarth G. 2010. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464:1293-1300. doi: 10.1038/nature08933.
8. Brennand K, Huangfu D, Melton D. 2007. All beta cells contribute equally to islet growth and maintenance. PLOS Biology 5:e163. doi: 10.1371/journal.pbio.0050163.
9. Brissova M, Aamodt K, Brahmachary P, Prasad N, Hong JY, Dai C, Mellati M, Shostak A, Poffenberger G, Aramandla R, Levy SE, Powers AC. 2014. Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes beta cell regeneration. Cell Metabolism 19:498-511. doi: 10.1016/j.cmet.2014.02.001.
10. Calderon B, Suri A, Unanue ER. 2006. In CD4+ T-cell-induced diabetes, macrophages are the final effector cells that mediate islet beta-cell killing: studies from an acute model. The American Journal of Pathology 169:2137-2147. doi: 10.2353/ajpath.2006.060539.
11. Cardozo AK, Heimberg H, Heremans Y, Leeman R, Kutlu B, Kruhøffer M, Ørntoft T, Eizirik DL. 2001. A comprehensive analysis of cytokine-induced and nuclear factor-kappa B-dependent genes in primary rat pancreatic beta-cells. The Journal of Biological Chemistry 276:48879-48886. doi: 10.1074/jbc.M108658200.
12. Chapuy B, McKeown MR, Lin CY, Monti S, Roemer MG, Qi J, Rahl PB, Sun HH, Yeda KT, Doench JG, Reichert E, Kung AL, Rodig SJ, Young RA, Shipp MA, Bradner JE. 2013. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24:777-790. doi: 10.1016/j.ccr.2013.11.003.
13. Chen LF, Williams SA, Mu Y, Nakano H, Duerr JM, Buckbinder L, Greene WC. 2005. NF-kappa B Rel A phosphorylation regulates Rel A acetylation. Molecular and Cellular Biology 25:7966-7975. doi: 10.1128/MCB.25. 18.7966-7975.2005.
14. Christensen DP, Gysemans C, Lundh M, Dahllof MS, Noesgaard D, Schmidt SF, Mandrup S, Birkbak N, Workman CT, Piemonti L, Blaabjerg L, Monzani V, Fossati G, Mascagni P, Paraskevas S, Aikin RA, Billestrup N, Grunnet LG, Dinarello CA, Mathieu C, Mandrup-Poulsen T. 2014. Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and beta-cell protection. Proceedings of the National Academy of Sciences of USA 111:1055-1059. doi: 10.1073/pnas.1320850111.
15. Clardy SM, Keliher EJ, Mohan JF, Sebas M, Benoist C, Mathis D, Weissleder R. 2014. Fluorescent exendin-4 derivatives for pancreatic beta-cell analysis. Bioconjugate Chemistry 25:171-177. doi: 10.1021/bc4005014.
16. Cnop M, Welsh N, Jonas JC, Jörns A, Lenzen S, Eizirik DL. 2005. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97-S107. doi: 10.2337/ diabetes.54.suppl_2.S97.
17. D'Alise AM, Auyeung V, Feuerer M, Nishio J, Fontenot J, Benoist C, Mathis D. 2008. The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors. Proceedings of the National Academy of Sciences of USA 105:19857-19862. doi: 10.1073/pnas.0810713105.
18. Dai FF, Zhang Y, Kang Y, Wang Q, Gaisano HY, Braunewell KH, Chan CB, Wheeler MB. 2006. The neuronal Ca2+ sensor protein visinin-like protein-1 is expressed in pancreatic islets and regulates insulin secretion. The Journal of Biological Chemistry 281:21942-21953. doi: 10.1074/jbc.M512924200.
19. Dawson MA, Kouzarides T. 2012. Cancer epigenetics: from mechanism to therapy. Cell 150:12-27. doi: 10.1016/ j.cell.2012.06.013.
20. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Chapman TD, Roberts EJ, Soden PE, Auger KR, Mirguet O, Doehner K, Delwel R, Burnett AK, Jeffrey P, Drewes G, Lee K, Huntly BJ, Kouzarides T. 2011. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478:529-533. doi: 10.1038/nature10509.
21. De León DD, Deng S, Madani R, Ahima RS, Drucker DJ, Stoffers DA. 2003. Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. Diabetes 52:365-371. doi: 10.2337/diabetes.52.2.365.
22. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS. 2011. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904-917. doi: 10.1016/j.cell.2011.08.017.
23. Dirice E, Kahraman S, Jiang W, El OA, De Jesus DF, Teo AK, Hu J, Kawamori D, Gaglia JL, Mathis D, Kulkarni RN. 2013. Soluble factors secreted by T-cells promote beta-cell proliferation. Diabetes 63:188-202. doi: 10.2337/ db13-0204.
24. Dittmer S, Kovacs Z, Yuan SH, Siszler G, Kögl M, Summer H, Geerts A, Golz S, Shioda T, Methner A. 2011. TOX3 is a neuronal survival factor that induces transcription depending on the presence of CITED1 or phosphorylated CREB in the transcriptionally active complex. Journal of Cell Science 124:252-260. doi: 10.1242/jcs.068759.
25. Eldor R, Yeffet A, Baum K, Doviner V, Amar D, Ben-Neriah Y, Christofori G, Peled A, Carel JC, Boitard C, Klein T, Serup P, Eizirik DL, Melloul D. 2006. Conditional and specific NF-kappa B blockade protects pancreatic beta cells from diabetogenic agents. Proceedings of the National Academy of Sciences of USA 103:5072-5077. doi: 10.1073/pnas.0508166103.
26. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE. 2010. Selective inhibition of BET bromodomains. Nature 468:1067-1073. doi: 10.1038/nature09504.
27. Fu W, Ergun A, Lu T, Hill JA, Haxhinasto S, Fassett MS, Gazit R, Adoro S, Glimcher L, Chan S, Kastner P, Rossi D, Collins JJ, Mathis D, Benoist C. 2012a. A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells. Nature Immunology 13:972-980. doi: 10.1038/ni.2420.
28. Fu W, Wojtkiewicz G, Weissleder R, Benoist C, Mathis D. 2012b. Early window of diabetes determinism in NOD mice, dependent on the complement receptor CRIg, identified by noninvasive imaging. Nature Immunology 13:361-368. doi: 10.1038/ni.2233.
29. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, Mazloom AR, Ma'ayan A, Chua WJ, Hansen TH, Turley SJ, Merad M, Randolph GJ, Immunological Genome Consortium. 2012. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nature Immunology 13:1118-1128. doi: 10.1038/ni.2419.
30. Gilmore TD. 2006. Introduction to NF-kappa B: players, pathways, perspectives. Oncogene 25:6680-6684. doi: 10.1038/sj.onc.1209954.
31. Hargreaves DC, Horng T, Medzhitov R. 2009. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138:129-145. doi: 10.1016/j.cell.2009.05.047.
32. Hill T, Krougly O, Nikkoopour E, Bellmore S, Lee-Chan E, Fouser LA, Hill DJ, Singh B. 2013. The involvement of interleukin-22 in the expression of pancreatic beta cell regenerative Reg genes. Cell Regen 2:2. doi: 10.1186/ 2045-9769-2-2.
33. Hirayama I, Tamemoto H, Yokota H, Kubo SK, Wang J, Kuwano H, Wang J, Kuwano H, Nagamachi Y, Takeuchi T, Izumi T. 1999. Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and-2. Diabetes 48:1237-1244. doi: 10.2337/diabetes. 48.6.1237.
34. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V, Sigova AA, Hoke HA, Young RA. 2013. Super-enhancers in the control of cell identity and disease. Cell 155:934-947. doi: 10.1016/j.cell.2013.09.053.
35. Huang B, Yang XD, Zhou MM, Ozato K, Chen LF. 2009. Brd4 coactivates transcriptional activation of NF-kappa B via specific binding to acetylated Rel A. Molecular and Cellular Biology 29:1375-1387. doi: 10.1128/ MCB.01365-08.
36. Huszarik K, Wright B, Keller C, Nikoopour E, Krougly O, Lee-Chan E, Qin HY, Cameron MJ, Gurr WK, Hill DJ, Sherwin RS, Kelvin DJ, Singh B. 2010. Adjuvant immunotherapy increases beta cell regenerative factor Reg2 in the pancreas of diabetic mice. The Journal of Immunology 185:5120-5129. doi: 10.4049/jimmunol.1001596.
37. Hutchings P, Rosen H, O'Reilly L, Simpson E, Gordon S, Cooke A. 1990. Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages. Nature 348:639-641. doi: 10.1038/348639a0.
38. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. 2005. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Molecular Cell 19:523-534. doi: 10.1016/j.molcel.2005.06.027.
39. Jansen A, Homo-Delarche F, Hooijkaas H, Leenen PJ, Dardenne M, Drexhage HA. 1994. Immunohistochemical characterization of monocytes-macrophages and dendritic cells involved in the initiation of the insulitis and beta-cell destruction in NOD mice. Diabetes 43:667-675. doi: 10.2337/diab.43.5.667.
40. Jun HS, Santamaria P, Lim HW, Zhang ML, Yoon JW. 1999a. Absolute requirement of macrophages for the development and activation of beta-cell cytotoxic CD8+ T-cells in T-cell receptor transgenic NOD mice. Diabetes 48:34-42. doi: 10.2337/diabetes.48.1.34.
41. Jun HS, Yoon CS, Zbytnuik L, van Rooijen N, Yoon JW. 1999b. The role of macrophages in T cell-mediated autoimmune diabetes in nonobese diabetic mice. The Journal of Experimental Medicine 189:347-358. doi: 10.1084/jem.189.2.347.
42. Katz JD, Wang B, Haskins K, Benoist C, Mathis D. 1993. Following a diabetogenic T cell from genesis through pathogenesis. Cell 74:1089-1100. doi: 10.1016/0092-8674(93)90730-E.
43. Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, Chan L. 2003. Neuro D-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nature Medicine 9:596-603. doi: 10.1038/nm867.
44. Kouzarides T. 2000. Acetylation: a regulatory modification to rival phosphorylation? The EMBO Journal 19:1176-1179. doi: 10.1093/emboj/19.6.1176.
45. Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D. 2011. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proceedings of the National Academy of Sciences of USA 108:11548-11553. doi: 10.1073/pnas.1108924108.
46. Li DS, Yuan YH, Tu HJ, Liang QL, Dai LJ. 2009. A protocol for islet isolation from mouse pancreas. Nature Protocols 4:1649-1652. doi: 10.1038/nprot.2009.150.
47. Liu JL, Cui W, Li B, Lu Y. 2008. Possible roles of reg family proteins in pancreatic islet cell growth. Endocrine, Metabolic & Immune Disorders Drug Targets 8:1-10. doi: 10.2174/187153008783928361.
48. Lockwood WW, Zejnullahu K, Bradner JE, Varmus H. 2012. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proceedings of the National Academy of Sciences of USA 109:19408-19413. doi: 10.1073/pnas.1216363109.
49. Lone AM, Taskén K. 2013. Proinflammatory and immunoregulatory roles of eicosanoids in T cells. Frontiers in Immunology 4:130. doi: 10.3389/fimmu.2013.00130.
50. Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA. 2013. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153:320-334. doi: 10.1016/j.cell.2013.03.036.
51. Mele DA, Salmeron A, Ghosh S, Huang HR, Bryant BM, Lora JM. 2013. BET bromodomain inhibition suppresses TH17-mediated pathology. The Journal of Experimental Medicine 210:2181-2190. doi: 10.1084/jem.20130376.
52. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, Sims RJ III. 2011. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proceedings of the National Academy of Sciences of USA 108:16669-16674. doi: 10.1073/pnas.1108190108.
53. Muller S, Filippakopoulos P, Knapp S. 2011. Bromodomains as therapeutic targets. Expert Reviews in Molecular Medicine 13:e29. doi: 10.1017/S1462399411001992.
54. Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A. 2010. Suppression of inflammation by a synthetic histone mimic. Nature 468:1119-1123. doi: 10.1038/nature09589.
55. Nowak DE, Tian B, Jamaluddin M, Boldogh I, Vergara LA, Choudhary S, Brasier AR. 2008. Rel A Ser276 phosphorylation is required for activation of a subset of NF-kappa B-dependent genes by recruiting cyclin-dependent kinase 9/cyclin T1 complexes. Molecular and Cellular Biology 28:3623-3638. doi: 10.1128/MCB.01152-07.
56. Pagliuca FW, Melton DA. 2013. How to make a functional beta-cell. Development 140:2472-2483. doi: 10.1242/ dev.093187.
57. Parker SC, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, Akiyama JA, van Bueren KL, Chines PS, Narisu N, NISC Comparative Sequencing Program, Black BL, Visel A, Pennacchio LA, Collins FS, National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program Authors, NISC Comparative Sequencing Program Authors. 2013. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proceedings of the National Academy of Sciences of USA 110:17921-17926. doi: 10.1073/pnas.1317023110.
58. Parsa R, Andresen P, Gillett A, Mia S, Zhang XM, Mayans S, Holmberg D, Harris RA. 2012. Adoptive transfer of immunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice. Diabetes 61:2881-2892. doi: 10.2337/db11-1635.
59. Patel MC, Debrosse M, Smith M, Dey A, Huynh W, Sarai N, Heightman TD, Tamura T, Ozato K. 2013. BRD4 coordinates recruitment of pause release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription elongation of interferon-stimulated genes. Molecular and Cellular Biology 33:2497-2507. doi: 10.1128/MCB.01180-12.
60. Prinjha RK, Witherington J, Lee K. 2012. Place your BETs: the therapeutic potential of bromodomains. Trends in Pharmacological Sciences 33:146-153. doi: 10.1016/j.tips.2011.12.002.
61. Ramirez-Carrozzi VR, Braas D, Bhatt DM, Cheng CS, Hong C, Doty KR, Black JC, Hoffmann A, Carey M, Smale ST. 2009. A unifying model for the selective regulation of inducible transcription by Cp G islands and nucleosome remodeling. Cell 138:114-128. doi: 10.1016/j.cell.2009.04.020.
62. Reich M, Liefeld T, Gould J, Lerner J, Tamayo P, Mesirov JP. 2006. Gene Pattern 2.0. Nature Genetics 38:500-501. doi: 10.1038/ng0506-500.
63. Rezende LF, Stoppiglia LF, Souza KL, Negro A, Langone F, Boschero AC. 2007. Ciliary neurotrophic factor promotes survival of neonatal rat islets via the BCL-2 anti-apoptotic pathway. The Journal of Endocrinology 195:157-165. doi: 10.1677/JOE-07-0016.
64. Ricklin D, Hajishengallis G, Yang K, Lambris JD. 2010. Complement: a key system for immune surveillance and homeostasis. Nature Immunology 11:785-797. doi: 10.1038/ni.1923.
65. Rink JS, Chen X, Zhang X, Kaufman DB. 2012. Conditional and specific inhibition of NF-kappa B in mouse pancreatic beta cells prevents cytokine-induced deleterious effects and improves islet survival posttransplant. Surgery 151:330-339. doi: 10.1016/j.surg.2011.07.011.
66. Schaefer CF, Anthony K, Krupa S, Buchoff J, Day M, Hannay T, Buetow KH. 2009. PID: the Pathway Interaction Database. Nucleic Acids Research 37:D674-D679. doi: 10.1093/nar/gkn653.
67. Seal J, Lamotte Y, Donche F, Bouillot A, Mirguet O, Gellibert F, Nicodeme E, Krysa G, Kirilovsky J, Beinke S, McCleary S, Rioja I, Bamborough P, Chung CW, Gordon L, Lewis T, Walker AL, Cutler L, Lugo D, Wilson DM, Witherington J, Lee K, Prinjha RK. 2012. Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A). Bioorganic & Medicinal Chemistry Letters 22:2968-2972. doi: 10.1016/j.bmcl.2012.02.041.
68. Serhan CN. 2011. The resolution of inflammation: the devil in the flask and in the details. FASEB Journal 25:1441-1448. doi: 10.1096/fj.11-0502ufm.
69. Sherry NA, Kushner JA, Glandt M, Kitamura T, Brillantes AM, Herold KC. 2006. Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes. Diabetes 55:3238-3245. doi: 10.2337/db05-1034.
70. Shi J, Vakoc CR. 2014. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Molecular Cell 54:728-736. doi: 10.1016/j.molcel.2014.05.016.
71. Shih HP, Wang A, Sander M. 2013. Pancreas organogenesis: from lineage determination to morphogenesis. Annual Review of Cell and Developmental Biology 29:81-105. doi: 10.1146/annurev-cellbio-101512-122405.
72. Sreenan S, Pick AJ, Levisetti M, Baldwin AC, Pugh W, Polonsky KS. 1999. Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse. Diabetes 48:989-996. doi: 10.2337/ diabetes.48.5.989.
73. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. 2005. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences of USA 102:15545-15550. doi: 10.1073/pnas.0506580102.
74. Takahashi T, Matsumoto S, Matsushita M, Kamachi H, Tsuruga Y, Kasai H, Watanabe M, Ozaki M, Furukawa H, Umezawa K, Todo S. 2010. Donor pretreatment with DHMEQ improves islet transplantation. The Journal of Surgical Research 163:e23-e34. doi: 10.1016/j.jss.2010.04.044.
75. Unno M, Itoh T, Watanabe T, Miyashita H, Moriizumi S, Teraoka H, Yonekura H, Okamoto H. 1992. Islet beta-cell regeneration and reg genes. Advances in Experimental Medicine and Biology 321:61-66. doi: 10.1007/ 978-1-4615-3448-8_8.
76. Unno M, Nata K, Noguchi N, Narushima Y, Akiyama T, Ikeda T, Nakagawa K, Takasawa S, Okamoto H. 2002. Production and characterization of Reg knockout mice: reduced proliferation of pancreatic beta-cells in Reg knockout mice. Diabetes 51(Suppl 3):S478-S483. doi: 10.2337/diabetes.51.2007.S478.
77. Vallabhapurapu S, Karin M. 2009. Regulation and function of NF-kappa B transcription factors in the immune system. Annual Review of Immunology 27:693-733. doi: 10.1146/annurev.immunol.021908.132641.
78. Vehik K, Dabelea D. 2011. The changing epidemiology of type 1 diabetes: why is it going through the roof? Diabetes/Metabolism Research and Reviews 27:3-13. doi: 10.1002/dmrr.1141.
79. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA. 2013. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153:307-319. doi: 10.1016/j.cell.2013.03.035.
80. Winzell MS, Ahren B. 2007. Role of VIP and PACAP in islet function. Peptides 28:1805-1813. doi: 10.1016/ j.peptides.2007.04.024.
81. Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D. 2010. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32:815-827. doi: 10.1016/j.immuni.2010.06.001.
82. Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, Song Z, El-Gohary Y, Prasadan K, Shiota C, Gittes GK. 2014. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proceedings of the National Academy of Sciences of USA 111:E1211-E1220. doi: 10.1073/pnas.1321347111.
83. Zhang G, Liu R, Zhong Y, Plotnikov AN, Zhang W, Zeng L, Rusinova E, Gerona-Nevarro G, Moshkina N, Joshua J, Chuang PY, Ohlmeyer M, He JC, Zhou MM. 2012. Down-regulation of NF-kappa B transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. The Journal of Biological Chemistry 287:28840-28851. doi: 10.1074/jbc.M112.359505.
84. Zhao R, Nakamura T, Fu Y, Lazar Z, Spector DL. 2011. Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activation. Nature Cell Biology 13:1295-1304. doi: 10.1038/ncb2341.
85. Zou Z, Huang B, Wu X, Zhang H, Qi J, Bradner J, Nair S, Chen LF. 2014. Brd4 maintains constitutively active NF-kappa B in cancer cells by binding to acetylated Rel A. Oncogene 33:2395-2404. doi: 10.1038/onc.2013.179.
86. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, Vakoc CR. 2011. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478:524-528. doi: 10.1038/ nature10334.