JMJD3 in the regulation of human diseases

Abstract

In recent years, many studies have shown that histone methylation plays an important role in maintaining the active and silent state of gene expression in human diseases. The Jumonji domain-containing protein D3 (JMJD3), specifically demethylate di- and trimethyllysine 27 on histone H3 (H3K27me2/3), has been widely studied in immune diseases, infectious diseases, cancer, developmental diseases, and aging related diseases. We will focus on the recent advances of JMJD3 function in human diseases, and looks ahead to the future of JMJD3 gene research in this review.

Key words： histone methylation; JMJD3; epigenetics; human diseases

References

1 Agger K, Cloos PAC, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K (2009) The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev 23:1171–1176. https://doi.org/10.1101/gad.510809

2 Agherbi H, Gaussmann-Wenger A, Verthuy C, Chasson L, Serrano M, Djabali M (2009) Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence. PLoS ONE 4:e5622. https://doi.org/10.1371/journal.pone.0005622

3 Alexaki VI, Fodelianaki G, Neuwirth A, Mund C, Kourgiantaki A, Ieronimaki E, Lyroni K, Troullinaki M, Fujii C, Kanczkowski W (2018) DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway. Mol Psychiatry 23:1410–1420. https://doi.org/10.1038/mp.2017.167

4 Anderton JA, Bose S, Vockerodt M, Vrzalikova K, Wei W, Kuo M, Helin K, Christensen J, Rowe M, Murray PG (2011) The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin’s Lymphoma. Oncogene 30:2037–2043. https://doi.org/10.1038/onc.2010.579

5 Arcipowski KM, Martinez CA, Ntziachristos P (2016) Histone demethylases in physiology and cancer: a tale of two enzymes, JMJD3 and UTX. Curr Opin Genet Dev 36:59–67. https://doi.org/10.1016/j.gde.2016.03.010

6 Arnold SJ, Hofmann UK, Bikoff EK, Robertson EJ (2008) Pivotal roles for eomesodermin during axis formation, epithelium-tomesenchyme transition and endoderm specification in the mouse. Development 135:501–511. https://doi.org/10.1242/dev.014357

7 Arthur JSC, Ley SC (2013) Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 13:679–692. https://doi.org/10.1038/nri3495

8 Backe MB, Andersson JL, Bacos K, Christensen DP, Hansen JB, Dorosz JJ, Gajhede M, Dahlby T, Bysani M, Kristensen LH (2018) Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function. Mol Cell Endocrinol 460:47–56. https://doi.org/10.1016/j.mce.2017.07.001

9 Baronchelli S, La Spada A, Ntai A, Barbieri A, Conforti P, Jotti GS, Redaelli S, Bentivegna A, de Blasio P, Biunno I (2017) Epigenetic and transcriptional modulation of WDR5, a chromatin remodeling protein, in Huntington’s disease human induced pluripotent stem cell (hiPSC) model. Mol Cell Neurosci 82:46–57. https://doi.org/10.1016/j.mcn.2017.04.013

10 Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenführ M, Maertens G, Banck M, Zhou M-M, Walsh MJ (2009) Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev 23:1177–1182. https://doi.org/10.1101/gad.511109

11 Barski A, Cuddapah S, Cui K, Roh T-Y, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837. https://doi.org/10.1016/j.cell.2007.05.009

12 Belver L, Ferrando A (2016) The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer 16:494–507. https://doi.org/10.1038/nrc.2016.63

13 Bergmann C, Brandt A, Merlevede B, Hallenberger L, Dees C, Wohlfahrt T, Pötter S, Zhang Y, Chen C-W, Mallano T (2018) The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis 77:150–158. https://doi.org/10.1136/annrheumdis-2017-211501

14 Bianchi-Smiraglia A, Lipchick BC, Nikiforov MA (2017) The Immortal Senescence. Methods Mol Biol 1534:1–15. https://doi.org/10.1007/978-1-4939-6670-7_1

15 Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine J-C (2007) The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 21:525–530. https://doi.org/10.1101/gad.415507

16 Burchfield JS, Li Q, Wang HY, Wang R-F (2015) JMJD3 as an epigenetic regulator in development and disease. Int J Biochem Cell Biol 67:148–157. https://doi.org/10.1016/j.biocel.2015.07. 006

17 Burgess SL, Saleh M, Cowardin CA, Buonomo E, Noor Z, Watanabe K, Abhyankar M, Lajoie S, Wills-Karp M, Petri WA (2016) Role of serum amyloid A, granulocyte-macrophage colony-stimulating factor, and bone marrow granulocyte-monocyte precursor expansion in segmented filamentous bacterium-mediated protection from Entamoeba histolytica. Infect Immun 84:2824–2832. https://doi.org/10.1128/IAI.00316-16

18 Cao H, Alrejaye N, Klein OD, Goodwin AF, Oberoi S (2017) A review of craniofacial and dental findings of the RASopathies. Orthod Craniofac Res 20(Suppl 1):32–38. https://doi.org/10.1111/ocr.12144

19 Chen Z, Zang J, Whetstine J, Hong X, Davrazou F, Kutateladze TG, Simpson M, Mao Q, Pan CH, Dai S (2006) Structural insights into histone demethylation by JMJD2 family members. Cell 125:691–702. https://doi.org/10.1016/j.cell.2006.04.024

20 Chen C, Wu M, Zhang W, Lu W, Zhang M, Zhang Z, Zhang X, Yuan Z (2016) MicroRNA-939 restricts Hepatitis B virus by targeting Jmjd3-mediated and C/EBPα-coordinated chromatin remodeling. Sci Rep 6:35974. https://doi.org/10.1038/srep35974

21 Chen X, Xiu M, Xing J, Yu S, Min D, Guo F (2017) Lanthanum chloride inhibits LPS mediated expressions of pro-inflammatory cytokines and adhesion molecules in HUVECs: involvement of NF-kB-Jmjd3 signaling. Cell Physiol Biochem 42:1713–1724. https://doi.org/10.1159/000479439

22 Chen Y, Liu Z, Pan T, Chen E, Mao E, Chen Y, Tan R, Wang X, Tian R, Liu J (2018) JMJD3 is involved in neutrophil membrane proteinase 3 overexpression during the hyperinflammatory response in early sepsis. Int Immunopharmacol 59:40–46. https://doi.org/10.1016/j.intimp.2018.03.027

23 Clevers H, Nusse R (2012) Wnt/β-catenin signaling and disease. Cell 149:1192–1205. https://doi.org/10.1016/j.cell.2012.05.012

24 Cribbs A, Hookway ES, Wells G, Lindow M, Obad S, Oerum H, Prinjha RK, Athanasou N, Sowman A, Philpott M (2018) Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells. J Biol Chem 293:2422–2437. https://doi.org/10.1074/jbc.RA117.000698

25 Das ND, Jung KH, Chai YG (2010) The role of NF-kB and H3K27me3 demethylase, Jmjd3, on the anthrax lethal toxin tolerance of RAW 264.7 cells. PLoS ONE 5:e9913. https://doi.org/10.1371/journal.pone.0009913

26 Das ND, Jung KH, Choi MR, Yoon HS, Kim SH, Chai YG (2012) Gene networking and inflammatory pathway analysis in a JMJD3 knockdown human monocytic cell line. Cell Biochem Funct 30:224–232. https://doi.org/10.1002/cbf.1839

27 Das A, Das ND, Jung KH, Park JH, Lee HT, Han D, Choi MR, Kang SC, Chai YG (2013) Proteomic changes induced by histone demethylase JMJD3 in TNF alpha-treated human monocytic (THP-1) cells. Mol Immunol 56:113–122. https://doi.org/10.1016/j.molimm.2013.04.013

28 Das A, Arifuzzaman S, Yoon T, Kim SH, Chai JC, Lee YS, Jung KH, Chai YG (2017) RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor. Sci Rep 7:6554. https://doi.org/10.1038/s41598-017-06914-5

29 Daures M, Idrissou M, Judes G, Rifaï K, Penault-Llorca F, Bignon Y-J, Guy L, Bernard-Gallon D (2018) A new metabolic gene signature in prostate cancer regulated by JMJD3 and EZH2. Oncotarget 9:23413–23425. https://doi.org/10.18632/oncotarget. 25182

30 David CJ, Massagué J (2018) Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol 19:419–435. https://doi.org/10.1038/s41580-018-0007-0

31 de Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130:1083–1094. https://doi.org/10.1016/j.cell.2007.08.019

32 de Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, Bucci G, Caganova M, Notarbartolo S, Casola S (2009) Jmjd3 contributes to the control of gene expression in LPSactivated macrophages. EMBO J 28:3341–3352. https://doi.org/10.1038/emboj.2009.271

33 Doñas C, Carrasco M, Fritz M, Prado C, Tejón G, Osorio-Barrios F, Manríquez V, Reyes P, Pacheco R, Bono MR (2016) The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. J Autoimmun 75:105–117. https://doi.org/10.1016/j.jaut.2016.07.011

34 Doorbar J, Egawa N, Griffin H, Kranjec C, Murakami I (2015) Human papillomavirus molecular biology and disease association. Rev Med Virol 25(Suppl 1):2–23. https://doi.org/10.1002/rmv.1822

35 Ene CI, Edwards L, Riddick G, Baysan M, Woolard K, Kotliarova S, Lai C, Belova G, Cam M, Walling J (2012) Histone demethylase Jumonji D3 (JMJD3) as a tumor suppressor by regulating p53 protein nuclear stabilization. PLoS ONE 7:e51407. https://doi.org/10.1371/journal.pone.0051407

36 Espín-Palazón R, Traver D (2016) The NF-kB family: key players during embryonic development and HSC emergence. Exp Hematol 44:519–527. https://doi.org/10.1016/j.exphem.2016.03.010

37 Estarás C, Akizu N, García A, Beltrán S, de La Cruz X, Martínez-Balbás MA (2012) Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program. Development 139:2681–2691. https://doi.org/10.1242/dev.078345

38 Estarás C, Fueyo R, Akizu N, Beltrán S, Martínez-Balbás MA (2013) RNA polymerase II progression through H3K27me3-enriched gene bodies requires JMJD3 histone demethylase. Mol Biol Cell 24:351–360. https://doi.org/10.1091/mbc.E12-07-0561

39 Feinberg AP (2018) The key role of epigenetics in human disease prevention and mitigation. N Engl J Med 378:1323–1334. https://doi.org/10.1056/NEJMra1402513

40 Gan X, Wang H, Yu Y, Yi W, Zhu S, Li E, Liang Y (2017) Epigenetically repressing human cytomegalovirus lytic infection and reactivation from latency in THP-1 model by targeting H3K9 and H3K27 histone demethylases. PLoS ONE 12:e0175390. https://doi.org/10.1371/journal.pone.0175390

41 Gomez-Sanchez JA, Gomis-Coloma C, Morenilla-Palao C, Peiro G, Serra E, Serrano M, Cabedo H (2013) Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge. Brain 136:2262–2278. https://doi.org/10.1093/brain/awt130

42 Guo Z, Lu J, Li J, Wang P, Li Z, Zhong Y, Guo K, Wang J, Ye J, Liu P (2018) JMJD3 inhibition protects against isoproterenol-induced cardiac hypertrophy by suppressing β-MHC expression. Mol Cell Endocrinol 477:1–14. https://doi.org/10.1016/j.mce.2018.05.009

43 Ha S-D, Cho W, Kim SO (2017) HDAC8 prevents anthrax lethal toxin-induced cell cycle arrest through silencing PTEN in human monocytic THP-1 cells. Toxins (Basel).https://doi.org/10.3390/toxins9050162

44 Hanisch U-K (2014) Linking STAT and TLR signaling in microglia: a new role for the histone demethylase Jmjd3. J Mol Med 92:197–200. https://doi.org/10.1007/s00109-014-1122-9

45 He R, Feng J, Xun Q, Qin Q, Hu C (2013) High-intensity training induces EIB in rats through neuron; transdifferentiation of adrenal medulla chromaffin cells. Am J Physiol Lung Cell Mol Physiol 304:L602–L612. https://doi.org/10.1152/ajplung.00406.2012

46 He C, Larson-Casey JL, Gu L, Ryan AJ, Murthy S, Carter AB (2016) Cu,Zn-superoxide dismutase-mediated redox regulation of jumonji domain containing 3 modulates macrophage polarization and pulmonary fibrosis. Am J Respir Cell Mol Biol 55:58–71. https://doi.org/10.1165/rcmb.2015-0183OC

47 Holla S, Prakhar P, Singh V, Karnam A, Mukherjee T, Mahadik K, Parikh P, Singh A, Rajmani RS, Ramachandra SG (2016) MUSASHI-mediated expression of JMJD3, a H3K27me3 demethylase, is involved in foamy macrophage generation during mycobacterial infection. PLoS Pathog 12:e1005814. https://doi.org/10.1371/journal.ppat.1005814

48 Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K (2007) Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci USA 104:18439–18444. https://doi.org/10.1073/pnas.0707292104

49 Hong Z, Li H, Li L, Wang W, Xu T (2017) Different expression patterns of histone H3K27 demethylases in renal cell carcinoma and bladder cancer. Cancer Biomark 18:125–131. https://doi.org/10.3233/CBM-160003

50 Hsu P, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157:1262–1278. https://doi.org/10.1016/j.cell.2014.05.010

51 Hsu AT, Lupancu TJ, Lee M-C, Fleetwood AJ, Cook AD, Hamilton JA, Achuthan A (2018) Epigenetic and transcriptional regulation of IL4-induced CCL17 production in human monocytes and murine macrophages. J Biol Chem 293:11415–11423. https://doi.org/10.1074/jbc.RA118.002416

52 Hu S, Han C, Hu JH, Zhu HJ (2017) Research progress on histone demethylase JMJD3. Biotechnol Bull 33(10):1–7

53 Inoue S-I, Takahara S, Yoshikawa T, Niihori T, Yanai K, Matsubara Y, Aoki Y (2017) Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice. Hum Mol Genet 26:4715–4727. https://doi.org/10.1093/hmg/ddx354

54 Ishii M, Wen H, Corsa CAS, Liu T, Coelho AL, Allen RM, Carson WF, Cavassani KA, Li X, Lukacs NW (2009) Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 114:3244–3254. https://doi.org/10.1182/blood-2009-04-217620

55 Jia W, Wu W, Yang D, Xiao C, Su Z, Huang Z, Li Z, Qin M, Huang M, Liu S (2018) Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis. FASEB J 32:4031–4042. https://doi.org/10.1096/fj.201701483R

56 Jin Q, Martinez CA, Arcipowski KM, Zhu Y, Gutierrez-Diaz BT, Wang KK, Johnson MR, Volk AG, Wang F, Wu J (2019) USP7 cooperates with NOTCH1 to drive the oncogenic transcriptional program in T-cell leukemia. Clin Cancer Res 25:222–239. https://doi.org/10.1158/1078-0432.CCR-18-1740

57 Kartikasari AER, Zhou JX, Kanji MS, Chan DN, Sinha A, Grapin-Botton A, Magnuson MA, Lowry WE, Bhushan A (2013) The histone demethylase Jmjd3 sequentially associates with the transcription factors Tbx3 and Eomes to drive endoderm differentiation. EMBO J 32:1393–1408. https://doi.org/10.1038/emboj.2013.78

58 Kim SW, Yoon S-J, Chuong E, Oyolu C, Wills AE, Gupta R, Baker J (2011) Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs. Dev Biol 357:492–504. https://doi.org/10.1016/j.ydbio.2011.06.009

59 Klose RJ, Kallin EM, Zhang Y (2006) JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 7:715–727. https://doi.org/10.1038/nrg1945

60 Kruidenier L, Chung C-W, Cheng Z, Liddle J, Che K, Joberty G, Bantscheff M, Bountra C, Bridges A, Diallo H (2012) A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488:404–408. https://doi.org/10.1038/nature11262

61 LaMere SA, Thompson RC, Meng X, Komori HK, Mark A, Salomon DR (2017) H3K27 methylation dynamics during CD4 T cell activation: regulation of JAK/STAT and IL12RB2 expression by JMJD3. J Immunol 199:3158–3175. https://doi.org/10.4049/jimmunol.1700475

62 Lee K, Na W, Lee JY, Na J, Cho H, Wu H, Yune TY, Kim W-S, Ju B-G (2012) Molecular mechanism of Jmjd3-mediated interleukin-6 gene regulation in endothelial cells underlying spinal cord injury. J Neurochem 122:272–282. https://doi.org/10.1111/j.1471-4159.2012.07786.x

63 Lee H-Y, Choi K, Oh H, Park Y-K, Park H (2014a) HIF-1-dependent induction of Jumonji domain-containing protein (JMJD) 3 under hypoxic conditions. Mol Cells 37:43–50. https://doi.org/10.14348/molcells.2014.2250

64 Lee HT, Kim SK, Kim SH, Kim K, Lim CH, Park J, Roh T-Y, Kim N, Chai YG (2014b) Transcription-related element gene expression pattern differs between microglia and macrophages during inflammation. Inflamm Res 63:389–397. https://doi.org/10.1007/s00011-014-0711-y

65 Lee JY, Na WH, Choi HY, Lee KH, Ju BG, Yune TY (2016) Jmjd3 mediates blood–spinal cord barrier disruption after spinal cord injury by regulating MMP-3 and MMP-9 expressions. Neurobiol Dis 95:66–81. https://doi.org/10.1016/j.nbd.2016.07.015

66 Lee M-C, Saleh R, Achuthan A, Fleetwood AJ, Förster I, Hamilton JA, Cook AD (2018) CCL17 blockade as a therapy for osteoarthritis pain and disease. Arthritis Res Ther 20:62. https://doi.org/10.1186/s13075-018-1560-9

67 Li Q, Zou J, Wang M, Ding X, Chepelev I, Zhou X, Zhao W, Wei G, Cui J, Zhao K(2014) Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nat Commun 5:5780. https://doi.org/10.1038/ncomms6780

68 Li Y, Zhang M, Sheng M, Zhang P, Chen Z, Xing W, Bai J, Cheng T, Yang F-C, Zhou Y (2018) Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia. J Cancer Res Clin Oncol 144:1065–1077. https://doi.org/10.1007/s00432-018-2631-7

69 Li S-H, Lu H-I, Chen Y-H, Lo C-M, Huang W-T, Tien W-Y, Lan Y-C, Tsai H-T, Chen C-H (2019) JMJD3 expression is an independent prognosticator in patients with esophageal squamous cell carcinoma. Surgery 165:946–952. https://doi.org/10.1016/j.surg.2018.11.015

70 Liang S, Yao Q, Wei D, Liu M, Geng F, Wang Q, Wang Y-S (2019) KDM6B promotes ovarian cancer cell migration and invasion by induced transforming growth factor-β1 expression. J Cell Biochem 120:493–506. https://doi.org/10.1002/jcb.27405

71 Lochmann TL, Powell KM, Ham J, Floros KV, Heisey DAR, Kurupi RIJ, Calbert ML, Ghotra MS, Greninger P, Dozmorov M (2018) Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma. Sci Transl Med 10: eaao4680. https://doi.org/10.1126/scitranslmed.aao4680

72 Lulla RR, Saratsis AM, Hashizume R (2016) Mutations in chromatin machinery and pediatric high-grade glioma. Sci Adv 2:e1501354. https://doi.org/10.1126/sciadv.1501354

73 Luo X, Yang D, Wu W, Long F, Xiao C, Qin M, Law BY, Suguro R, Xu X, Qu L (2018) Critical role of histone demethylase Jumonji domain-containing protein 3 in the regulation of neointima formation following vascular injury. Cardiovasc Res 114:1894–1906. https://doi.org/10.1093/cvr/cvy176

74 Majumder S, Thieme K, Batchu SN, Alghamdi TA, Bowskill BB, Kabir MG, Liu Y, Advani SL, White KE, Geldenhuys L (2018) Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease. J Clin Investig 128:483–499. https://doi.org/10.1172/JCI95946

75 Mathur R, Sehgal L, Havranek O, Köhrer S, Khashab T, Jain N, Burger JA, Neelapu SS, Davis RE, Samaniego F (2017) Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs. Haematologica 102:373–380. https://doi.org/10.3324/haematol.2016.144964

76 Mei JH, Tang G, Wang Q, Wen PQ, Xu MG, Cui D, Ma DL, Liu C, Wang GB (2017) Role of ash2 (absent, small, or homeotic)-like and Jumonji domain-containing protein 3 on histone methylation of interferon-gamma gene and their associations with vascular damage of Kawasaki disease. Zhonghua Xin Xue Guan Bing Za Zhi 45:791–798. https://doi.org/10.3760/cma.j.issn.0253-3758.2017.09.012

77 Meng Y-H, Zhou W-J, Jin L-P, Liu L-B, Chang K-K, Mei J, Li H, Wang J, Li D-J, Li M-Q (2017) RANKL-mediated harmonious dialogue between fetus and mother guarantees smooth gestation by inducing decidual M2 macrophage polarization. Cell Death Dis 8: e3105. https://doi.org/10.1038/cddis.2017.505

78 Merkwirth C, Jovaisaite V, Durieux J, Matilainen O, Jordan SD, Quiros PM, Steffen KK, Williams EG, Mouchiroud L, Tronnes SU (2016) Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165:1209–1223. https://doi.org/10.1016/j.cell.2016.04.012

79 Miller SA, Weinmann AS (2009) An essential interaction between T-box proteins and histone-modifying enzymes. Epigenetics 4:85–88. https://doi.org/10.4161/epi.4.2.8111

80 Miller SA, Weinmann AS (2010) Molecular mechanisms by which T-bet regulates T-helper cell commitment. Immunol Rev 238:233–246. https://doi.org/10.1111/j.1600-065X.2010.00952.x

81 Mohan M, Kaushal D, Aye PP, Alvarez X, Veazey RS, Lackner AA (2013) Focused examination of the intestinal epithelium reveals transcriptional signatures consistent with disturbances in enterocyte maturation and differentiation during the course of SIV infection. PLoS ONE 8:e60122. https://doi.org/10.1371/journal.pone.0060122

82 Mozzetta C, Boyarchuk E, Pontis J, Ait-Si-Ali S (2015) Sound of silence: the properties and functions of repressive Lys methyltransferases. Nat Rev Mol Cell Biol 16:499–513. https://doi.org/10.1038/nrm4029

83 Murray PJ (2017) Macrophage polarization. Annu Rev Physiol 79:541–566. https://doi.org/10.1146/annurev-physiol-022516-034339

84 Na J, Lee K, Na W, Shin J-Y, Lee M-J, Yune TY, Lee HK, Jung H-S, Kim WS, Ju B-G (2016) Histone H3K27 demethylase JMJD3 in cooperation with NF-kB regulates keratinocyte wound healing. J Investig Dermatol 136:847–858. https://doi.org/10.1016/j.jid.2015.11.029

85 Naruse C, Shibata S, Tamura M, Kawaguchi T, Abe K, Sugihara K, Kato T, Nishiuchi T, Wakana S, Ikawa M (2017) New insights into the role of Jmjd3 and Utx in axial skeletal formation in mice. FASEB J 31:2252–2266. https://doi.org/10.1096/fj.201600642

86 RNtziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L, Loizou E, Holmfeldt L, Strikoudis A, King B (2014) Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514:513–517. https://doi.org/10.1038/nature13605

87 Nusse R, Clevers H (2017) Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169:985–999. https://doi.org/10.1016/j.cell.2017.05.016

88 Odorisio T (2016) Epigenetic control of skin re-epithelialization: the NF-kB/JMJD3 connection. J Investig Dermatol 136:738–740. https://doi.org/10.1016/j.jid.2016.01.010

89 Ohguchi H, Harada T, Sagawa M, Kikuchi S, Tai Y-T, Richardson PG, Hideshima T, Anderson KC (2017) KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia 31:2661–2669. https://doi.org/10.1038/leu.2017.141

90 Ohtani K, Zhao C, Dobreva G, Manavski Y, Kluge B, Braun T, Rieger MA, Zeiher AM, Dimmeler S (2013) Jmjd3 controls mesodermal and cardiovascular differentiation of embryonic stem cells. Circ Res 113:856–862. https://doi.org/10.1161/CIRCRESAHA.113. 302035

91 Park DH, Hong SJ, Salinas RD, Liu SJ, Sun SW, Sgualdino J, Testa G, Matzuk MM, Iwamori N, Lim DA (2014) Activation of neuronal gene expression by the JMJD3 demethylase is required for postnatal and adult brain neurogenesis. Cell Rep 8:1290–1299. https://doi.org/10.1016/j.celrep.2014.07.060

92 Park W-Y, Hong B-J, Lee J, Choi C, Kim M-Y (2016) H3K27 demethylase JMJD3 employs the NF-κB and BMP signaling pathways to modulate the tumor microenvironment and promote melanoma progression and metastasis. Cancer Res 76:161–170. https://doi.org/10.1158/0008-5472.CAN-15-0536

93 Park JW, Cho H, Oh H, Kim J-Y, Seo S-B (2018) AURKA suppresses leukemic THP-1 cell differentiation through inhibition of the KDM6B pathway. Mol Cells 41:444–453. https://doi.org/10.14348/molcells.2018.2311

94 Pasparakis M (2009) Regulation of tissue homeostasis by NF-kB signalling: implications for inflammatory diseases. Nat Rev Immunol 9:778–788. https://doi.org/10.1038/nri2655

95 Penas C, Navarro X (2018) Epigenetic modifications associated to neuroinflammation and neuropathic pain after neural trauma. Front Cell Neurosci 12:158. https://doi.org/10.3389/fncel.2018. 00158

96 Pereira F, Barbáchano A, Silva J, Bonilla F, Campbell MJ, Muñoz A, Larriba MJ (2011) KDM6B/JMJD3 histone demethylase is induced by vitamin D and modulates its effects in colon cancer cells. Hum Mol Genet 20:4655–4665. https://doi.org/10.1093/hmg/ddr399

97 Pereira F, Barbáchano A, Singh PK, Campbell MJ, Muñoz A, Larriba MJ (2012) Vitamin D has wide regulatory effects on histone demethylase genes. Cell Cycle 11:1081–1089. https://doi.org/10.4161/cc.11.6.19508

98 Perrigue PM, Silva ME, Warden CD, Feng NL, Reid MA, Mota DJ, Joseph LP, Tian YI, Glackin CA, Gutova M (2015) The histone demethylase jumonji coordinates cellular senescence including secretion of neural stem cell-attracting cytokines. Mol Cancer Res 13:636–650. https://doi.org/10.1158/1541-7786. MCR-13-0268

99 Pham D, Yu Q, Walline CC, Muthukrishnan R, Blum JS, Kaplan MH (2013) Opposing roles of STAT4 and Dnmt3a in Th1 gene regulation. J Immunol 191:902–911. https://doi.org/10.4049/jimmunol.1203229

100 Pinheiro I, Malhão F, Madureira TV, João Rocha M, Monteiro RAF, Rocha E (2015) Ethinylestradiol exposure of primary culture brown trout hepatocytes induce morphological changes in peroxisomes. Microsc Microanal 21(Suppl 5):81–82. https://doi.org/10.1017/S143192761501421X