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Histone demethylase Jumonji D3 (JMJD3/KDM6B) at the nexus of epigenetic regulation of inflammation and the aging process

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Abstract

Histone methylation is involved in the epigenetic control of immune responses and cellular senescence. Jumonji domain-containing protein 3 (JMJD3), also called lysine-specific demethylase 6B (KDM6b), is an inducible histone demethylase which enhances immune responses and can trigger cellular senescence. JMJD3 potentiates gene expression by demethylating repressive H3K27me3 epigenetic marks in promoters and gene bodies. Moreover, JMJD3 also stimulates transcription in a demethylase-independent manner by mediating interactions between chromatin modifiers. JMJD3 can enhance both pro-inflammatory and anti-inflammatory responses by targeting distinct transcription factors in a context-dependent manner in gene promoters. For instance, JMJD3 can induce macrophage M2 polarization via STAT6 signaling. JMJD3 also interacts with T-bet factor and induces Th1 differentiation of CD4+ T cells. Moreover, JMJD3 can activate TGF-β signaling through the SMAD3 pathway. Conversely, JMJD3 displaces polycomb complexes from the INK4 box, which induces the expression of INK4a and triggers cellular senescence. JMJD3 can also enhance the nuclear localization of p53 and thus regulate its function. The control of INK4 box and p53 is closely related to the regulation of the aging process. We will briefly review the inducible properties of JMJD3 expression and then focus on the role of JMJD3 in the regulation of inflammation and senescence through different signaling pathways. We emphasize that an inflammatory milieu and cellular stress can enhance immune responses and provoke cellular senescence via epigenetic regulation through JMJD3 activation.

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References

  1. Kondilis-Mangum HD, Wade PA (2013) Epigenetics and the adaptive immune response. Mol Aspects Med 34:813–825

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Stender JD, Glass CK (2013) Epigenomic control of the innate immune response. Curr Opin Pharmacol 13:582–587

    Article  PubMed  CAS  Google Scholar 

  3. Gonzalo S (2010) Epigenetic alterations in aging. J Appl Physiol 109:586–597

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Han S, Brunet A (2012) Histone methylation makes its mark on longevity. Trends Cell Biol 22:42–49

    Article  PubMed  PubMed Central  Google Scholar 

  5. Natoli G (2009) Control of NF-κB-dependent transcriptional responses by chromatin organization. Cold Spring Harb Perspect Biol 1:a000224

    Article  PubMed  PubMed Central  Google Scholar 

  6. Johansson C, Tumber A, Che K, Cain P, Nowak R, Gileadi C, Oppermann U (2014) The roles of Jumonji-type oxygenases in human disease. Epigenomics 6:89–120

    Article  PubMed  CAS  Google Scholar 

  7. Shpargel KB, Sengoku T, Yokoyama S, Magnuson T (2012) UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. PLoS Genet 8:e1002964

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Welstead GG, Creyghton MP, Bilodeau S, Cheng AW, Markoulaki S, Young RA, Jaenisch R (2012) X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner. Proc Natl Acad Sci U S A 109:13004–13009

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Morales Torres C, Laugesen A, Helin K (2013) Utx is required for proper induction of ectoderm and mesoderm during differentiation of embryonic stem cells. PLoS One 8:e60020

    Article  PubMed  PubMed Central  Google Scholar 

  10. Estaras C, Fueyo R, Akizu N, Beltran S, Martinez-Balbas MA (2013) RNA polymerase II progression through H3K27me3-enriched gene bodies requires JMJD3 histone demethylase. Mol Biol Cell 24:351–360

    Article  PubMed  PubMed Central  Google Scholar 

  11. Miller SA, Mohn SE, Weinmann AS (2010) Jmjd3 and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Mol Cell 40:594–605

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K (2007) UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449:731–734

    Article  PubMed  CAS  Google Scholar 

  13. 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

    Article  PubMed  Google Scholar 

  14. Lan F, Peter E, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I et al (2007) A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 449

  15. Simon JA, Kingston RE (2013) Occupying chromatin: polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put. Mol Cell 49:808–824

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Ishii M, Wen H, Corsa CA, Liu T, Coelho AL, Allen RM, Carson WF, Cavassani KA, Li X, Lukacs NW et al (2009) Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 114:3244–3254

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Shan J, Fu L, Balasubramanian MN, Anthony T, Kilberg MS (2012) ATF4-dependent regulation of the JMJD3 gene during amino acid deprivation can be rescued in ATF-deficient cells by inhibition of deacetylation. J Biol Chem 287:36393–36403

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Lee HY, Choi K, Oh H, Park YK, Park H (2014) HIF-1-dependent induction of Jumonji domain-containing protein (JMJD) 3 under hypoxic conditions. Mol Cells 37:43–50

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Przanowski P, Dabrowski M, Ellert-Miklaszewska A, Kloss M, Mieczkowski J, Kaza B, Ronowicz A, Hu F, Piotrowski A, Kettenmann H et al (2014) The signal transducers Stat1 and Stat3 and their novel target Jmjd3 drive the expression of inflammatory genes in microglia. J Mol Med (Berlin) 92:239–254

    Article  CAS  Google Scholar 

  20. Gargalovic PS, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Baruch-Oren T, Berliner JA, Kirchgessner TG et al (2006) The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler Thromb Vasc Biol 26:2490–2496

    Article  PubMed  CAS  Google Scholar 

  21. Iwasaki Y, Suganami T, Hachiya R, Shirakawa I, Kim-Saijo M, Tanaka M, Hamaguchi M, Takai-Igarashi T, Nakai M, Miyamoto Y et al (2014) Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages. Diabetes 63:152–161

    Article  PubMed  CAS  Google Scholar 

  22. Scholz CC, Taylor CT (2013) Targeting the HIF pathway in inflammation and immunity. Curr Opin Pharmacol 13:646–653

    Article  PubMed  CAS  Google Scholar 

  23. Chen S, Ma J, Wu F, Xiong L, Ma H, Xu W, Lv R, Li X, Villen J, Gygi SP et al (2012) The histone H3 Lys 27 demethylase JMJD3 regulates gene expression by impacting transcriptional elongation. Genes Dev 26:1364–1375

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, Bucci G, Caganova M, Notarbartolo S, Casola S et al (2009) Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J 28:3341–3352

    Article  PubMed  PubMed Central  Google Scholar 

  25. 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

    Article  PubMed  CAS  Google Scholar 

  26. Lee K, Na W, Lee JY, Na J, Cho H, Wu H, Yune TY, Kim WS, Ju BG (2012) Molecular mechanism of Jmjd3-mediated interleukin-6 gene regulation in endothelial cells underlying spinal cord injury. J Neurochem 122:272–282

    Article  PubMed  CAS  Google Scholar 

  27. Diamant G, Dikstein R (2013) Transcriptional control by NF-κB: elongation in focus. Biochim Biophys Acta 1829:937–945

    Article  PubMed  CAS  Google Scholar 

  28. 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 α-treated human monocytic (THP-1) cells. Mol Immunol 56:113–122

    Article  PubMed  CAS  Google Scholar 

  29. Pertel T, Hausmann S, Morger D, Züger S, Guerra J, Lascano J, Reinhard C, Santoni FA, Uchil PD, Chatel L et al (2011) TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 472:361–365

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Ajibade AA, Wang HY, Wang RF (2013) Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol 34:307–316

    Article  PubMed  CAS  Google Scholar 

  31. Casseta L, Cassol E, Poli G (2011) Macrophage polarization in health and disease. Sci World J 11:2391–2402

    Article  Google Scholar 

  32. Tugal D, Liao X, Jain MK (2013) Transcriptional control of macrophage polarization. Arterioscler Thromb Vasc Biol 33:1135–1144

    Article  PubMed  CAS  Google Scholar 

  33. Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T et al (2010) The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11:936–944

    Article  PubMed  CAS  Google Scholar 

  34. Tang Y, Li T, Li J, Yang J, Liu H, Zhang XJ, Le W (2014) Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease. Cell Death Differ 21:369–380

    Article  PubMed  CAS  Google Scholar 

  35. Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A (2013) Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25:1939–1948

    Article  PubMed  CAS  Google Scholar 

  36. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Yoshimura A, Wakabayashi Y, Mori T (2010) Cellular and molecular basis for the regulation of inflammation by TGF-β. J Biochem 147:781–792

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Bonniaud P, Margetts PJ, Ask K, Flanders K, Gauldie J, Kolb M (2005) TGF-β and Smad3 signaling link inflammation to chronic fibrogenesis. J Immunol 175:5390–5395

    Article  PubMed  CAS  Google Scholar 

  39. Santibanez JF, Quintanilla M, Bernabeu C (2011) TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 121:233–251

    Article  CAS  Google Scholar 

  40. Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S (2012) TGF-β—an excellent servant but a bad master. J Transl Med 10:183

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461

    Article  PubMed  CAS  Google Scholar 

  42. Yoshimura A, Muto G (2011) TGF-β function in immune suppression. Curr Top Microbiol Immunol 350:127–147

    PubMed  CAS  Google Scholar 

  43. Dahle O, Kumar A, Kuehn MR (2010) Nodal signaling recruits the histone demethylase Jmjd3 to counteract polycomb-mediated repression at target genes. Sci Signal 3:ra48

  44. Estaras C, Akizu N, Garcia A, Beltran S, de la Cruz X, Martinez-Balbas MA (2012) Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activates the neural development program. Development 139:2681–2691

    Article  PubMed  CAS  Google Scholar 

  45. Huang Y, Min S, Lui Y, Sun J, Su X, Liu Y, Zhang Y, Han D, Che Y, Zhao C et al (2012) Global mapping of H3K4me3 and H3K27me3 reveals chromatin state-based regulation of human monocyte-derived dendritic cells in different environments. Genes Immun 13:311–320

    Article  PubMed  CAS  Google Scholar 

  46. Miller SA, Weinmann AS (2010) Molecular mechanisms by which T-bet regulates T-helper cell commitment. Immunol Rev 238:233–246

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Oestreich KJ, Weinmann AS (2012) Transcriptional mechanisms that regulate T helper 1 cell differentiation. Curr Opin Immunol 24:191–195

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Takashima Y, Suzuki A (2013) Regulation of organogenesis and stem cell properties by T-box transcription factors. Cell Mol Life Sci 70:3929–3945

    Article  PubMed  CAS  Google Scholar 

  49. Kartikasari AE, 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Jacobs JJ, Keblusek P, Robanus-Maandag E, Kristel P, Lingbeek M, Nederlof PM, van Welsem T, van de Vijver MJ, Koh EY, Daley GQ et al (2000) Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) and is amplified in a subset of human breast cancers. Nat Genet 26:291–299

    Article  PubMed  CAS  Google Scholar 

  51. Brummelkamp TR, Kortlever RM, Lingbeek M, Trettel F, MacDonald ME, van Lohuizen M, Bernards R (2002) TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence. J Biol Chem 277:6567–6572

    Article  PubMed  CAS  Google Scholar 

  52. Sidler C, Woycicki R, Ilnytskyy Y, Metz G, Kovalchuk I, Kovalchuk O (2013) Immunosenescence is associated with altered gene expression and epigenetic regulation in primary and secondary immune organs. Front Genet 4:211

    Article  PubMed  PubMed Central  Google Scholar 

  53. Salminen A, Kauppinen A, Kaarniranta K (2012) Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal 24:835–845

    Article  PubMed  CAS  Google Scholar 

  54. Sahin E, DePinho RA (2012) Axis of ageing: telomeres, p53 and mitochondria. Nat Rev Mol Cell Biol 13:397–404

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Rufini A, Tucci P, Celardo I, Melino G (2013) Senescence and aging: the critical roles of p53. Oncogene 32:5129–5143

    Article  PubMed  CAS  Google Scholar 

  56. Gu B, Zhu WG (2012) Surf the post-translational modification network of p53 regulation. Int J Biol Sci 8:672–684

    Article  PubMed  PubMed Central  Google Scholar 

  57. Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS, McKinney K, Tempst P, Prives C, Gamblin SJ et al (2004) Regulation of p53 activity through lysine methylation. Nature 432:353–360

    Article  PubMed  CAS  Google Scholar 

  58. West LE, Gozani O (2011) Regulation of p53 function by lysine methylation. Epigenomics 3:361–369

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Green DR, Kroemer G (2009) Cytoplasmic functions of the tumour suppressor p53. Nature 458:1127–1130

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Sola S, Xavier JM, Santos DM, Aranha MM, Morgado AL, Jepsen K, Rodrigues CM (2011) p53 interaction with JMJD3 results in its nuclear distribution during mouse neural stem cell differentiation. PLoS One 6:e18421

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Zhang Y, Xiong Y, Yarbrough WG (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92:725–734

    Article  PubMed  CAS  Google Scholar 

  62. Ene CI, Edwards L, Riddick G, Baysan M, Woolard K, Kotliarova S, Lai C, Belova G, Cam M, Walling J et al (2012) Histone demethylase Jumonji D3 (JMJD3) as a tumor suppressor by regulating p53 protein nuclear stabilization. PLoS One 7(12):e51407

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Chang BD, Watanabe K, Broude EV, Fang J, Poole JC, Kalinichenko TV, Roninson IB (2000) Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A 97:4291–4296

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Feng Z, Hu W, Teresky AK, Hernando E, Cordon-Cardo C, Arnold J, Levine AJ (2007) Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations. Proc Natl Acad Sci U S A 104:16633–16638

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Ohkusu-Tsukada K, Tsukada T, Isobe K (1999) Accelerated development and aging of the immune system in p53-deficient mice. J Immunol 163:1966–1972

    PubMed  CAS  Google Scholar 

  66. Kim WY, Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127:265–275

    Article  PubMed  CAS  Google Scholar 

  67. Aguilo F, Zhou MM, Walsh MJ (2011) Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression. Cancer Res 71:5365–5369

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  68. Simboeck E, Ribeiro JD, Teichmann S, Di Croce L (2011) Epigenetics and senescence: learning from the INK4-ARF locus. Biochem Pharmacol 82:1361–1370

    Article  PubMed  CAS  Google Scholar 

  69. Yap KL, Li S, Munoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM (2010) Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 38:662–674

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Kotake Y, Nakagawa T, Kitagawa K, Suzuki S, Liu N, Kitagawa M, Xiong Y (2011) Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene 30:1956–1962

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. Pasmant E, Sabbagh A, Vidaud M, Bieche I (2011) ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J 25:444–448

    Article  PubMed  CAS  Google Scholar 

  72. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Monch K, Minucci S, Porse BT, Marine JC et al (2007) The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 21:525–530

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  73. Agger K, Cloos PA, 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  75. 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

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was financially supported by the grants from the Academy of Finland, VTR funding from Kuopio University Hospital, and strategic funding for UEFBRAIN consortium from University of Eastern Finland. The authors thank Dr. Ewen MacDonald for checking the language of the manuscript.

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The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211, Kuopio, Finland

    Antero Salminen & Mikko Hiltunen

  2. Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211, Kuopio, Finland

    Kai Kaarniranta & Anu Kauppinen

  3. Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, FI-70029, Kuopio, Finland

    Kai Kaarniranta & Anu Kauppinen

  4. Department of Neurology, Kuopio University Hospital, P.O. Box 100, FI-70029, Kuopio, Finland

    Mikko Hiltunen

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Salminen, A., Kaarniranta, K., Hiltunen, M. et al. Histone demethylase Jumonji D3 (JMJD3/KDM6B) at the nexus of epigenetic regulation of inflammation and the aging process. J Mol Med 92, 1035–1043 (2014). https://doi.org/10.1007/s00109-014-1182-x

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