Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases
Antero Salminen1,*, Kai Kaarniranta2,3, Anu Kauppinen3,4
1Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland 2Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland 3Department of Ophthalmology, Kuopio University Hospital, Finland 4School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
Hypoxia is an environmental stress at high altitude and underground conditions but it is also present in many chronic age-related diseases, where blood flow into tissues is impaired. The oxygen-sensing system stimulates gene expression protecting tissues against hypoxic insults. Hypoxia stabilizes the expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls the expression of hundreds of survival genes related to e.g. enhanced energy metabolism and autophagy. Moreover, many stress-related signaling mechanisms, such as oxidative stress and energy metabolic disturbances, as well as the signaling cascades via ceramide, mTOR, NF-κB, and TGF-β pathways, can also induce the expression of HIF-1α protein to facilitate cell survival in normoxia. Hypoxia is linked to prominent epigenetic changes in chromatin landscape. Screening studies have indicated that the stabilization of HIF-1α increases the expression of distinct histone lysine demethylases (KDM). HIF-1α stimulates the expression of KDM3A, KDM4B, KDM4C, and KDM6B, which enhance gene transcription by demethylating H3K9 and H3K27 sites (repressive epigenetic marks). In addition, HIF-1α induces the expression of KDM2B and KDM5B, which repress transcription by demethylating H3K4me2,3 sites (activating marks). Hypoxia-inducible KDMs support locally the gene transcription induced by HIF-1α, although they can also control genome-wide chromatin landscape, especially KDMs which demethylate H3K9 and H3K27 sites. These epigenetic marks have important role in the control of heterochromatin segments and 3D folding of chromosomes, as well as the genetic loci regulating cell type commitment, proliferation, and cellular senescence, e.g. the INK4 box. A chronic stimulation of HIF-1α can provoke tissue fibrosis and cellular senescence, which both are increasingly present with aging and age-related diseases. We will review the regulation of HIF-1α-dependent induction of KDMs and clarify their role in pathological processes emphasizing that long-term stress-related insults can impair the maintenance of chromatin landscape and provoke cellular senescence and tissue fibrosis associated with aging and age-related diseases.
Figure 1. Induction of KDM expression by HIF-1α signaling. HIF-1α signaling can be activated by hypoxia and several stress-related signaling pathways, commonly called pseudohypoxia since they activate HIF-1α signaling in normoxia. KDMs induced by HIF-1α control the transcription of HIF-1α target genes but in addition, they can modify the global chromatin landscape provoking pathological changes linked to the aging process and age-related diseases. Abbreviations: HIF-1α, hypoxia-inducible factor-1α; HNE, 4-hydroxynonenal; JAK, Janus kinase; KDM, histone lysine demethylase; mTor, mammalian target of rapamycin; NF-κB, nuclear factor-κB; NO, nitric oxide; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; Smad3, SMAD family member 3; STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor-β.
Kaelin WG Jr, Ratcliffe PJ (2008). Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell, 30:393-402.
Taylor CT, McElwain JC (2010). Ancient atmospheres and the evolution of oxygen sensing via the hypoxia-inducible factor in metazoans. Physiology (Bethesda), 25:272-279.
Rytkönen KT, Williams TA, Renshaw GM, Primmer CR, Nikinmaa M (2011). Molecular evolution of the metazoan PHD-HIF oxygen-sensing system. Mol Biol Evol, 28:1913-1926.
Semenza GL (2012). Hypoxia-inducible factors in physiology and medicine. Cell, 148:399-408.
Ratcliffe PJ (2013). Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J Physiol, 591:2027-2042.
Bigham AW, Lee FS (2014). Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes Dev, 28:2189-2204.
Larson J, Drew KL, Folkow LP, Milton SL, Park TJ (2014). No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates. J Exp Biol, 217:1024-1039.
Semenza GL, Wang GL (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol, 12:5447-5454.
Wang GL, Semenza GL (1993). General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A, 90:4304-4308.
Wang GL, Semenza GL (1995). Purification and characterization of hypoxia-inducible factor 1. J Biol Chem, 270:1230-1237.
Wang GL, Jiang BH, Rue EA, Semenza GL (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A, 92:5510-5514.
Pugh CW, Tan CC, Jones RW, Ratcliffe PJ (1991). Functional analysis of an oxygen-regulated transcriptional enhancer lying 3' to the mouse erythropoietin gene. Proc Natl Acad Sci U S A, 88:10553-10557.
Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ (1994). Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3' enhancer. Proc Natl Acad Sci U S A, 91:6496-6500.
Ratcliffe PJ, O'Rourke JF, Maxwell PH, Pugh CW (1998). Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. J Exp Biol, 201:1153-1162.
Bruick RK, McKnight SL (2001). A conserved family of prolyl-4-hydroxylases that modify HIF. Science, 294:1337-1340.
Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR,et al. (2001). C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 107:43-54.
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ,et al. (2001). Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292:468-472.
Hausinger RP (2004). FeII/α-ketoglutarate-dependent hydroxylases and related enzymes. Crit Rev Biochem Mol Biol, 39:21-68.
McDonough MA, Loenarz C, Chowdhury R, Clifton IJ, Schofield CJ (2010). Structural studies on human 2-oxoglutarate dependent oxygenases. Curr Opin Struct Biol, 20:659-672.
Klose RJ, Kallin EM, Zhang Y (2006). JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet, 7:715-727.
Pastor WA, Aravind L, Rao A (2013). TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol, 14:341-356.
Salminen A, Kauppinen A, Kaarniranta K (2015). 2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: Potential role in the regulation of aging process. Cell Mol Life Sci, doi:10.1007/s00018-015-1978-z.
Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H,et al. (2001). Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature, 414:550-554.
Marxsen JH, Stengel P, Doege K, Heikkinen P, Jokilehto T, Wagner T,et al. (2004). Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-α-prolyl-4 hydroxylases. Biochem J, 381:761-767.
Loboda A, Jozkowicz A, Dulak J (2012). HIF-1 versus HIF-2 - is one more important than the other? Vascul Pharmacol, 56:245-251.
Rocha S (2007). Gene regulation under low oxygen: holding your breath for transcription. Trends Biochem Sci, 32:389-397.
Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J,et al. (2009). Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem, 284:16767-16775.
Majmundar AJ, Wong WJ, Simon MC (2010). Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell, 40:294-309.
Greer SN, Metcalf JL, Wang Y, Ohh M (2012). The updated biology of hypoxia-inducible factor. EMBO J, 31:2448-2460.
Nallamshetty S, Chan SY, Loscalzo J (2013). Hypoxia: a master regulator of microRNA biogenesis and activity. Free Radic Biol Med, 64:20-30.
Chan SY, Loscalzo J (2010). MicroRNA-210: a unique and pleiotropic hypoxamir. Cell Cycle, 9:1072-1083.
Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD,et al. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell, 7:77-85.
Koivunen P, Hirsilä M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J (2007). Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem, 282:4524-4532.
Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC,et al. (2005). Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum Mol Genet, 14:2231-2239.
Wilson WJ, Poellinger L (2002). The dietary flavonoid quercetin modulates HIF-1α activity in endothelial cells. Biochem Biophys Res Commun, 293:446-450.
Park SS, Bae I, Lee YJ (2008). Flavonoids-induced accumulation of hypoxia-inducible factor (HIF)-1α/2α is mediated through chelation of iron. J Cell Biochem, 103:1989-1998.
Fraisl P, Aragones J, Carmeliet P (2009). Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov, 8:139-152.
Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B (1998). Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1α/ARNT. EMBO J, 17:5085-5094.
Stiehl DP, Jelkmann W, Wenger RH, Hellwig-Bürgel T (2002). Normoxic induction of the hypoxia-inducible factor 1α by insulin and interleukin-1β involves the phosphatidylinositol 3-kinase pathway. FEBS Lett, 512:157-162.
Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E (2002). Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem, 277:27975-27981.
Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E,et al. (2000). Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev, 14:391-396.
Seok JK, Lee SH, Kim MJ, Lee YM (2014). MicroRNA-382 induced by HIF-1α is an angiogenic miR targeting the tumor suppressor phosphatase and tensin homolog. Nucleic Acids Res, 42:8062-8072.
Dodd KM, Yang J, Shen MH, Sampson JR, Tee AR (2015). mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene, 34:2239-2250.
Treins C, Murdaca J, Van Obberghen E, Giorgetti-Peraldi S (2006). AMPK activation inhibits the expression of HIF-1α induced by insulin and IGF-1. Biochem Biophys Res Commun, 342:1197-1202.
Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J (1999). p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1α) and enhance the transcriptional activity of HIF-1. J Biol Chem, 274:32631-32637.
Flügel D, Görlach A, Michiels C, Kietzmann T (2007). Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1α and mediates its destabilization in a VHL-independent manner. Mol Cell Biol, 27:3253-3265.
Haddad JJ, Harb HL (2005). Cytokines and the regulation of hypoxia-inducible factor (HIF)-1α. Int Immunopharmacol, 5:461-483.
Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V,et al. (2008). NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature, 453:807-811.
Sun H, Li XB, Meng Y, Fan L, Li M, Fang J (2013). TRAF6 upregulates expression of HIF-1α and promotes tumor angiogenesis. Cancer Res, 73:4950-4959.
Scharte M, Han X, Bertges DJ, Fink MP, Delude RL (2003). Cytokines induce HIF-1 DNA binding and the expression of HIF-1-dependent genes in cultured rat enterocytes. Am J Physiol Gastrointest Liver Physiol, 284:G373-G384.
Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L (2003). IL-1β-mediated up-regulation of HIF-1α via an NFκB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J, 17:2115-2117.
Sharma V, Dixit D, Koul N, Mehta VS, Sen E (2011). Ras regulates interleukin-1β-induced HIF-1α transcriptional activity in glioblastoma. J Mol Med (Berl), 89:123-136.
van Uden P, Kenneth NS, Rocha S (2008). Regulation of hypoxia-inducible factor-1α by NF-κB. Biochem J, 412:477-484.
Bandarra D, Biddlestone J, Mudie S, Müller HA, Rocha S (2015). HIF-1α restricts NF-κB-dependent gene expression to control innate immunity signals. Dis Model Mech, 8:169-181.
Jung JE, Kim HS, Lee CS, Shin YJ, Kim YN, Kang GH,et al. (2008). STAT3 inhibits the degradation of HIF-1α by pVHL-mediated ubiquitination. Exp Mol Med, 40:479-485.
McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM (2006). Transforming growth factor β1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem, 281:24171-24181.
Rozen-Zvi B, Hayashida T, Hubchak SC, Hanna C, Platanias LC, Schnaper HW (2013). TGF-β/Smad3 activates mammalian target of rapamycin complex-1 to promote collagen production by increasing HIF-1α expression. Am J Physiol Renal Physiol, 305:F485-F494.
Michaud MD, Robitaille GA, Gratton JP, Richard DE (2009). Sphingosine-1-phosphate: a novel nonhypoxic activator of hypoxia-inducible factor-1 in vascular cells. Arterioscler Thromb Vasc Biol, 29:902-908.
Nizet V, Johnson RS (2009). Interdependence of hypoxic and innate immune responses. Nat Rev Immunol, 9:609-617.
Mateo J, García-Lecea M, Cadenas S, Hernandez C, Moncada S (2003). Regulation of hypoxia-inducible factor-1α by nitric oxide through mitochondria-dependent and -independent pathways. Biochem J, 376:537-544.
Kietzmann T, Görlach A (2005). Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression. Semin Cell Dev Biol, 16:474-486.
Chua YL, Dufour E, Dassa EP, Rustin P, Jacobs HT, Taylor CT,et al. (2010). Stabilization of hypoxia-inducible factor-1α protein in hypoxia occurs independently of mitochondrial reactive oxygen species production. J Biol Chem, 285:31277-31284.
Hagen T (2012). Oxygen versus reactive oxygen in the regulation of HIF-1α: The balance tips. Biochem Res Int, 2012:436981.
Metzen E, Zhou J, Jelkmann W, Fandrey J, Brüne B (2003). Nitric oxide impairs normoxic degradation of HIF-1α by inhibition of prolyl hydroxylases Mol Biol Cell, 14:3470-3481.
Hickok JR, Vasudevan D, Antholine WE, Thomas DD (2013). Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem, 288:16004-16015.
Qutub AA, Popel AS (2008). Reactive oxygen species regulate hypoxia-inducible factor 1α differentially in cancer and ischemia. Mol Cell Biol, 28:5106-5119.
Geng H, Liu Q, Xue C, David LL, Beer TM, Thomas GV,et al. (2012). HIF1α protein stability is increased by acetylation at lysine 709. J Biol Chem, 287:35496-35505.
Xenaki G, Ontikatze T, Rajendran R, Stratford IJ, Dive C, Krstic-Demonacos M,et al. PCAF is an HIF-1α cofactor that regulates p53 transcriptional activity in hypoxia. Oncogene, 27:5785-5796.
Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW (2010). Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1α. Mol Cell, 38:864-878.
Chen R, Dioum EM, Hogg RT, Gerard RD, Garcia JA (2011). Hypoxia increases sirtuin 1 expression in a hypoxia-inducible factor-dependent manner. J Biol Chem, 286:13869-13878.
Chen S, Yin C, Lao T, Liang D, He D, Wang C,et al. (2015). AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol. Cell Cycle, 14:2520-2536.
Kato H, Tamamizu-Kato S, Shibasaki F (2004). Histone deacetylase 7 associates with hypoxia-inducible factor 1α and increases transcriptional activity. J Biol Chem, 279:41966-41974.
Minet E, Mottet D, Michel G, Roland I, Raes M, Remacle J,et al. (1999). Hypoxia-induced activation of HIF-1: role of HIF-1α-Hsp90 interaction. FEBS Lett, 460:251-256.
Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL (2007). RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α. Mol Cell, 25:207-217.
Liu YV, Hubbi ME, Pan F, McDonald KR, Mansharamani M, Cole RN,et al. (2007). Calcineurin promotes hypoxia-inducible factor 1α expression by dephosphorylating RACK1 and blocking RACK1 dimerization. J Biol Chem, 282:37064-37073.
Black JC, Van Rechem C, Whetstine JR (2012). Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell, 48:491-507.
Cloos PA, Christensen J, Agger K, Helin K (2008). Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev, 22:1115-1140.
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.
Sanchez-Fernandez EM, Tarhonskaya H, Al-Qahtani K, Hopkinson RJ, McCullagh JS, Schofield CJ,et al. (2013). Investigations on the oxygen dependence of a 2-oxoglutarate histone demethylase. Biochem J, 449:491-496.
Shmakova A, Batie M, Druker J, Rocha S (2014). Chromatin and oxygen sensing in the context of JmjC histone demethylases. Biochem J, 462:385-395.
Hancock RL, Dunne K, Walport LJ, Flashman E, Kawamura A (2015). Epigenetic regulation by histone demethylases in hypoxia. Epigenomics, doi:10.2217/EPI.15.24
Beyer S, Kristensen MM, Jensen KS, Johansen JV, Staller P (2008). The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF. J Biol Chem, 283:36542-36552.
Krieg AJ, Rankin EB, Chan D, Razorenova O, Fernandez S, Giaccia AJ (2010). Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1α enhances hypoxic gene expression and tumor growth. Mol Cell Biol, 30:344-353.
Sar A, Ponjevic D, Nguyen M, Box AH, Demetrick DJ (2009). Identification and characterization of demethylase JMJD1A as a gene upregulated in the human cellular response to hypoxia. Cell Tissue Res, 337:223-234.
Xia X, Lemieux ME, Li W, Carroll JS, Brown M, Liu XS,et al. (2009). Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci U S A, 106:4260-4265.
Yang J, Ledaki I, Turley H, Gatter KC, Montero JC, Li JL,et al. (2009). Role of hypoxia-inducible factors in epigenetic regulation via histone demethylases. Ann N Y Acad Sci, 1177:185-197.
Tausendschön M, Dehne N, Brüne B (2011). Hypoxia causes epigenetic gene regulation in macrophages by attenuating Jumonji histone demethylase activity. Cytokine, 53:256-262.
Fu L, Chen L, Yang J, Ye T, Chen Y, Fang J (2012). HIF-1α-induced histone demethylase JMJD2B contributes to the malignant phenotype of colorectal cancer cells via an epigenetic mechanism. Carcinogenesis, 33:1664-1673.
Wellmann S, Bettkober M, Zelmer A, Seeger K, Faigle M, Eltzschig HK,et al. (2008). Hypoxia upregulates the histone demethylase JMJD1A via HIF-1. Biochem Biophys Res Commun, 372:892-897.
Cheutin T, Cavalli G (2014). Polycomb silencing: from linear chromatin domains to 3D chromosome folding. Curr Opin Genet Dev, 25:30-37.
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.
Salminen A, Kaarniranta K, Hiltunen M, Kauppinen A (2014). Histone demethylase Jumonji D3 (JMJD3/KDM6B) at the nexus of epigenetic regulation of inflammation and the aging process. J Mol Med (Berl), 92:1035-1043.
Koivunen P, Hirsilä M, Kivirikko KI, Myllyharju J (2006). The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4-hydroxylases. J Biol Chem, 281:28712-28720.
Iacobas DA, Fan C, Iacobas S, Spray DC, Haddad GG (2006). Transcriptomic changes in developing kidney exposed to chronic hypoxia. Biochem Biophys Res Commun, 349:329-338.
Wikenheiser J, Wolfram JA, Gargesha M, Yang K, Karunamuni G, Wilson DL,et al. (2009). Altered hypoxia-inducible factor-1α expression levels correlate with coronary vessel anomalies. Dev Dyn, 238:2688-2700.
Chen H, Yan Y, Davidson TL, Shinkai Y, Costa M (2006). Hypoxic stress induces dimethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells. Cancer Res, 66:9009-9016.
Benlhabib H, Mendelson CR (2011). Epigenetic regulation of surfactant protein A gene (SP-A) expression in fetal lung reveals a critical role for Suv39h methyltransferases during development and hypoxia. Mol Cell Biol, 31:1949-1958.
Liu X, Chen Z, Xu C, Leng X, Cao H, Ouyang G,et al. (2015). Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation. Nucleic Acids Res, 43:5081-5098.
Johnson AB, Barton MC (2007). Hypoxia-induced and stress-specific changes in chromatin structure and function. Mutat Res, 618:149-162.
Watson JA, Watson CJ, McCann A, Baugh J (2010). Epigenetics, the epicenter of the hypoxic response. Epigenetics, 5:293-296.
Perez-Perri JI, Acevedo JM, Wappner P (2011). Epigenetics: new questions on the response to hypoxia. Int J Mol Sci, 12:4705-4721.
Semenza GL (2011). Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta, 1813:1263-1268.
Storey KB (2015). Regulation of hypometabolism: insights into epigenetic controls. J Exp Biol, 218:150-159.
Buffenstein R (2005). The naked mole-rat: a new long-living model for human aging research. J Gerontol A Biol Sci Med Sci, 60:1369-1377.
Lorenzen JM, Martino F, Thum T (2012). Epigenetic modifications in cardiovascular disease. Basic Res Cardiol., 107:245.
Wang J, Yu JT, Tan MS, Jiang T, Tan L (2013). Epigenetic mechanisms in Alzheimer's disease: implications for pathogenesis and therapy. Ageing Res Rev, 12:1024-1041.
Nguyen MP, Lee S, Lee YM (2013). Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics. Arch Pharm Res, 36:252-263.
Cedar H, Bergman Y (2009). Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet, 10:295-304.
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.
Johnson AB, Denko N, Barton MC (2008). Hypoxia induces a novel signature of chromatin modifications and global repression of transcription. Mutat Res, 640:174-179.
Toyokawa G, Cho HS, Iwai Y, Yoshimatsu M, Takawa M, Hayami S,et al. (2011). The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6. Cancer Prev Res (Phila), 4:2051-2061.
Young LC, Hendzel MJ (2013). The oncogenic potential of Jumonji D2 (JMJD2/KDM4) histone demethylase overexpression. Biochem Cell Biol, 91:369-377.
Awwad SW, Ayoub N (2015). Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway. Biol Open, 4:498-504.
Conde-Perezprina JC, Leon-Galvan MA, Konigsberg M (2012). DNA mismatch repair system: repercussions in cellular homeostasis and relationship with aging. Oxid Med Cell Longev, 2012:728430.
Perrigue PM, Silva ME, Warden CD, Feng NL, Reid MA, Mota DJ,et al. (2015). The histone demethylase jumonji coordinates cellular senescence including secretion of neural stem cell-attracting cytokines. Mol Cancer Res, 13:636-650.
Fähling M (2009). Surviving hypoxia by modulation of mRNA translation rate. J Cell Mol Med, 13:2770-2779.
Watson JA, Watson CJ, McCrohan AM, Woodfine K, Tosetto M, McDaid J,et al. (2009). Generation of an epigenetic signature by chronic hypoxia in prostate cells. Hum Mol Genet, 18:3594-3604.
Robinson CM, Neary R, Levendale A, Watson CJ, Baugh JA (2012). Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype. Respir Res, 13:74.
Schweizer S, Meisel A, Märschenz S (2013). Epigenetic mechanisms in cerebral ischemia. J Cereb Blood Flow Metab, 33:1335-1346.
Trojer P, Reinberg D (2007). Facultative heterochromatin: is there a distinctive molecular signature? Mol Cell, 28:1-13.
Beisel C, Paro R (2011). Silencing chromatin: comparing modes and mechanisms. Nat Rev Genet, 12:123-135.
Margueron R, Reinberg D (2011). The Polycomb complex PRC2 and its mark in life. Nature, 469:343-349.
Zofall M, Grewal SI (2006). Swi6/HP1 recruits a JmjC domain protein to facilitate transcription of heterochromatic repeats. Mol Cell, 22:681-692.
Lin CH, Paulson A, Abmayr SM, Workman JL (2012). HP1a targets the Drosophila KDM4A demethylase to a subset of heterochromatic genes to regulate H3K36me3 levels. PLoS One, 7:e39758.
Sdek P, Oyama K, Angelis E, Chan SS, Schenke-Layland K, MacLellan WR (2013). Epigenetic regulation of myogenic gene expression by heterochromatin protein 1α. PLoS One, 8:e58319.
Fodor BD, Kubicek S, Yonezawa M, O'Sullivan RJ, Sengupta R, Perez-Burgos L,et al. (2006). Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev, 20:1557-1562.
Slee RB, Steiner CM, Herbert BS, Vance GH, Hickey RJ, Schwarz T,et al. (2012). Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability. Oncogene, 31:3244-3253.
Li X, Liu L, Yang S, Song N, Zhou X, Gao J,et al. (2014). Histone demethylase KDM5B is a key regulator of genome stability. Proc Natl Acad Sci U S A, 111:7096-7101.
Abe Y, Rozqie R, Matsumura Y, Kawamura T, Nakaki R, Tsurutani Y,et al. (2015). JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis. Nat Commun, 6:7052.
Riedel CG, Dowen RH, Lourenco GF, Kirienko NV, Heimbucher T, West JA,et al. (2013). DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat Cell Biol, 15:491-501.
Mimura I, Nangaku M, Kanki Y, Tsutsumi S, Inoue T, Kohro T,et al. (2012). Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol Cell Biol, 32:3018-3032.
Crona F, Dahlberg O, Lundberg LE, Larsson J, Mannervik M (2013). Gene regulation by the lysine demethylase KDM4A in Drosophila. Dev Biol, 373:453-463.
Black JC, Manning AL, Van Rechem C, Kim J, Ladd B, Cho J,et al. (2013). KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell, 154:541-555.
Zheng H, Chen L, Pledger WJ, Fang J, Chen J (2014). p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression. Oncogene, 33:734-744.
Khoury-Haddad H, Guttmann-Raviv N, Ipenberg I, Huggins D, Jeyasekharan AD, Ayoub N (2014). PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair. Proc Natl Acad Sci U S A, 111:E728-E737.
Young LC, McDonald DW, Hendzel MJ (2013). Kdm4b histone demethylase is a DNA damage response protein and confers a survival advantage following γ-irradiation. J Biol Chem, 288:21376-21388.
Deaton AM, Bird A (2011). CpG islands and the regulation of transcription. Genes Dev, 25:1010-1022.
Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, Rose NR,et al. (2012). KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands. Elife, 1:e00205.
Wu X, Johansen JV, Helin K (2013). Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Mol Cell, 49:1134-1146.
Tzatsos A, Paskaleva P, Lymperi S, Contino G, Stoykova S, Chen Z,et al. (2011). Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells. J Biol Chem, 286:33061-33069.
Frescas D, Guardavaccaro D, Bassermann F, Koyama-Nasu R, Pagano M (2007). JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes. Nature, 450:309-313.
Tzatsos A, Pfau R, Kampranis SC, Tsichlis PN (2009). Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc Natl Acad Sci U S A, 106:2641-2646.
He J, Shen L, Wan M, Taranova O, Wu H, Zhang Y (2013). Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat Cell Biol, 15:373-384.
Liang G, He J, Zhang Y (2012). Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. Nat Cell Biol, 14:457-466.
Li Q, Shi L, Gui B, Yu W, Wang J, Zhang D,et al. (2011). Binding of the JmjC demethylase JARID1B to LSD1/NuRD suppresses angiogenesis and metastasis in breast cancer cells by repressing chemokine CCL14. Cancer Res, 71:6899-6908.
Klein BJ, Piao L, Xi Y, Rincon-Arano H, Rothbart SB, Peng D,et al. (2014). The histone-H3K4-specific demethylase KDM5B binds to its substrate and product through distinct PHD fingers. Cell Rep, 6:325-335.
Zhang Y, Liang J, Li Q (2014). Coordinated regulation of retinoic acid signaling pathway by KDM5B and polycomb repressive complex 2. J Cell Biochem, 115:1528-1538.
Wang X, Nagl NG, Wilsker D, Van Scoy M, Pacchione S, Yaciuk P,et al. (2004). Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Biochem J, 383:319-325.
Barrett A, Santangelo S, Tan K, Catchpole S, Roberts K, Spencer-Dene B,et al. (2007). Breast cancer associated transcriptional repressor PLU-1/JARID1B interacts directly with histone deacetylases. Int J Cancer, 121:265-275.
Krishnakumar R, Kraus WL (2010). PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. Mol Cell, 39:736-749.
Bueno MT, Richard S (2013). SUMOylation negatively modulates target gene occupancy of the KDM5B, a histone lysine demethylase. Epigenetics, 8:1162-1175.
Hendriks IA, Treffers LW, Verlaan-de Vries M, Olsen JV, Vertegaal AC (2015). SUMO-2 orchestrates chromatin modifiers in response to DNA damage. Cell Rep, http://creativecommons.org/licenses/by-nc-nd/3.0.
Schmitz SU, Albert M, Malatesta M, Morey L, Johansen JV, Bak M,et al. (2011). Jarid1b targets genes regulating development and is involved in neural differentiation. EMBO J, 30:4586-4600.
Albert M, Schmitz SU, Kooistra SM, Malatesta M, Morales Torres C,et al. (2013). The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3. PLoS Genet, 9:e1003461.
Saha B, Home P, Ray S, Larson M, Paul A, Rajendran G,et al. (2013). EED and KDM6B coordinate the first mammalian cell lineage commitment to ensure embryo implantation. Mol Cell Biol, 33:2691-2705.
Burgold T, Spreafico F, De Santa F, Totaro MG, Prosperini E, Natoli G,et al. (2008). The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment. PLoS One, 3:e3034.
Kartikasari AE, Zhou JX, Kanji MS, Chan DN, Sinha A, Grapin-Botton A,et al. (2013). The histone demethylase Jmjd3 sequentially associates with the transcription factors Tbx3 and Eomes to drive endoderm differentiation. EMBO J, 32:1393-1408.
Ohtani K, Zhao C, Dobreva G, Manavski Y, Kluge B, Braun T,et al. (2013). Jmjd3 controls mesodermal and cardiovascular differentiation of embryonic stem cells. Circ Res, 113:856-862.
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.
Miller SA, Weinmann AS (2009). An essential interaction between T-box proteins and histone-modifying enzymes. Epigenetics, 4:85-88.
Miller SA, Weinmann AS (2010). Molecular mechanisms by which T-bet regulates T-helper cell commitment. Immunol Rev, 238:233-246.
Collado M, Blasco MA, Serrano M (2007). Cellular senescence in cancer and aging. Cell, 130:223-233.
Leiser SF, Kaeberlein M (2010). The hypoxia-inducible factor HIF-1 functions as both a positive and negative modulator of aging. Biol Chem, 391:1131-1137.
Philipp EE, Abele D (2010). Masters of longevity: lessons from long-lived bivalves - a mini-review. Gerontology, 56:55-65.
Shams I, Avivi A, Nevo E (2004). Hypoxic stress tolerance of the blind subterranean mole rat: expression of erythropoietin and hypoxia-inducible factor 1α. Proc Natl Acad Sci U S A, 101:9698-9703.
Rivard A, Berthou-Soulie L, Principe N, Kearney M, Curry C, Branellec D,et al. (2000). Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. J Biol Chem, 275:29643-29647.
Ndubuizu OI, Chavez JC, LaManna JC (2009). Increased prolyl 4-hydroxylase expression and differential regulation of hypoxia-inducible factors in the aged rat brain. Am J Physiol Regul Integr Comp Physiol, 297:R158-R165.
Benderro GF, Lamanna JC (2011). Hypoxia-induced angiogenesis is delayed in aging mouse brain. Brain Res, 1389:50-60.
Demidenko ZN, Blagosklonny MV (2011). The purpose of the HIF-1/PHD feedback loop: to limit mTOR-induced HIF-1α. Cell Cycle. 10:1557-1562.
Finkel T, Holbrook NJ (2000). Oxidants, oxidative stress and the biology of ageing. Nature, 408:239-247.
Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T (2008). Activation of innate immunity system during aging: NF-κB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev, 7:83-105.
Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY,et al. (2009). Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev, 8:18-30.
Grainger DJ (2007). TGF-β and atherosclerosis in man. Cardiovasc Res, 74:213-222.
Symons JD, Abel ED (2013). Lipotoxicity contributes to endothelial dysfunction: a focus on the contribution from ceramide. Rev Endocr Metab Disord, 14:59-68.
Guarente L, Kenyon C (2000). Genetic pathways that regulate ageing in model organisms. Nature, 408:255-262.
Nicholls DG (2002). Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease. Int J Biochem Cell Biol, 34:1372-1381.
Shohet RV, Garcia JA (2007). Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia. J Mol Med (Berl), 85:1309-1315.
Arjamaa O, Nikinmaa M, Salminen A, Kaarniranta K. Regulatory role of HIF-1α in the pathogenesis of age-related macular degeneration (AMD). Ageing Res Rev, 8:349-358.
Semenza GL (2002). HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med, 8:S62-S67.
Luo R, Zhang W, Zhao C, Zhang Y, Wu H, Jin J,et al. (2015). Elevated endothelial hypoxia-inducible factor-1α contributes to glomerular injury and promotes hypertensive chronic kidney disease. Hypertension, 66:75-84.
Watson CJ, Collier P, Tea I, Neary R, Watson JA, Robinson C,et al. (2014). Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum Mol Genet, 23:2176-2188.
Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S,et al. (2009). Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol, 29:4467-4483.
Wierda RJ, Rietveld IM, van Eggermond MC, Belien JA, van Zwet EW, Lindeman JH,et al. (2015). Global histone H3 lysine 27 triple methylation levels are reduced in vessels with advanced atherosclerotic plaques. Life Sci, 129:3-9.
Greissel A, Culmes M, Napieralski R, Wagner E, Gebhard H, Schmitt M,et al. (2015). Alternation of histone and DNA methylation in human atherosclerotic carotid plaques. Thromb Haemost, 114:390-402.
Bell JT, Tsai PC, Yang TP, Pidsley R, Nisbet J, Glass D,et al. (2012). Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet, 8:e1002629.
McClay JL, Aberg KA, Clark SL, Nerella S, Kumar G, Xie LY,et al. (2014). A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects. Hum Mol Genet, 23:1175-1185.
Sun D, Yi SV (2015). Impacts of chromatin states and long-range genomic segments on aging and DNA methylation. PLoS One, 10:e0128517.
Shumaker DK, Dechat T, Kohlmaier A, Adam SA, Bozovsky MR, Erdos MR,et al. (2006). Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A, 103:8703-8708.
Heyn H, Moran S, Esteller M (2013). Aberrant DNA methylation profiles in the premature aging disorders Hutchinson-Gilford Progeria and Werner syndrome. Epigenetics, 8:28-33.
Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J,et al. (2015). A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science, 348:1160-1163.
Villeponteau B (1997). The heterochromatin loss model of aging. Exp Gerontol, 32:383-394.
Larson K, Yan SJ, Tsurumi A, Liu J, Zhou J, Gaur K,et al. (2012). Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet, 8:e1002473.
Tsurumi A, Li WX (2012). Global heterochromatin loss: a unifying theory of aging? Epigenetics, 7:680-688.
Feser J, Tyler J (2011). Chromatin structure as a mediator of aging. FEBS Lett, 585:2041-2048.
Illi B, Ciarapica R, Capogrossi MC.Chromatin methylation and cardiovascular aging. J Mol Cell Cardiol, 83:21-31.
Ollikainen M, Ismail K, Gervin K, Kyllönen A, Hakkarainen A, Lundbom J,et al. (2015). Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in monozygotic twins discordant for obesity and liver fat. Clin Epigenetics, 7:39.
Osawa T, Tsuchida R, Muramatsu M, Shimamura T, Wang F, Suehiro J,et al. (2013). Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages. Cancer Res, 73:3019-3028.
Fork C, Gu L, Hitzel J, Josipovic I, Hu J, SzeKa Wong M,et al. (2015). Epigenetic regulation of angiogenesis by JARID1B-induced repression of HOXA5. Arterioscler Thromb Vasc Biol, 35:1645-1652.
Ohtani K, Vlachojannis GJ, Koyanagi M, Boeckel JN, Urbich C, Farcas R,et al. (2011). Epigenetic regulation of endothelial lineage committed genes in pro-angiogenic hematopoietic and endothelial progenitor cells. Circ Res, 109:1219-1229.
Funayama R, Ishikawa F (2007). Cellular senescence and chromatin structure. Chromosoma, 116:431-440.
Chandra T, Ewels PA, Schoenfelder S, Furlan-Magaril M, Wingett SW, Kirschner K,et al. (2015). Global reorganization of the nuclear landscape in senescent cells. Cell Rep. 10:471-483.
Campisi J (2005). Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell, 120:513-522.
Jeyapalan JC, Sedivy JM (2008). Cellular senescence and organismal aging. Mech Ageing Dev, 129:467-474.
Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H (2011). Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci, 34:3-11.
Ovadya Y, Krizhanovsky V (2014). Senescent cells: SASPected drivers of age-related pathologies. Biogerontology, 15:627-642.
Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL (2014). Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care, 17:324-328.
Campisi J, Andersen JK, Kapahi P, Melov S (2011). Cellular senescence: a link between cancer and age-related degenerative disease? Semin Cancer Biol, 21:354-359.
Gil J, Peters G (2006). Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol, 7:667-677.
Popov N, Gil J (2010). Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health. Epigenetics, 5:685-690.
Aguilo F, Zhou MM, Walsh MJ (2011). Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression. Cancer Res, 71:5365-5369.
Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J,et al. (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.
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.
Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenführ M,et al. (2009). Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev, 23:1177-1182.
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.
Nijwening JH, Geutjes EJ, Bernards R, Beijersbergen RL (2011). The histone demethylase Jarid1b (Kdm5b) is a novel component of the Rb pathway and associates with E2f-target genes in MEFs during senescence. PLoS One, 6:e25235.
Chicas A, Kapoor A, Wang X, Aksoy O, Evertts AG, Zhang MQ,et al. (2012). H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. Proc Natl Acad Sci U S A, 109:8971-8976.
Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA,et al. (2003). Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell, 113:703-716.
Leontieva OV, Natarajan V, Demidenko ZN, Burdelya LG, Gudkov AV, Blagosklonny MV (2012). Hypoxia suppresses conversion from proliferative arrest to cellular senescence. Proc Natl Acad Sci U S A, 109:13314-13318.
Kilic Eren M, Tabor V (2014). The role of hypoxia inducible factor-1α in bypassing oncogene-induced senescence. PLoS One, 9:e101064.
Leontieva OV, Blagosklonny MV (2012). Hypoxia and gerosuppression: the mTOR saga continues. Cell Cycle, 11:3926-3931.
Ene CI, Edwards L, Riddick G, Baysan M, Woolard K, Kotliarova S,et al. (2012). Histone demethylase Jumonji D3 (JMJD3) as a tumor suppressor by regulating p53 protein nuclear stabilization. PLoS One, 7:e51407.
Palazon A, Goldrath AW, Nizet V, Johnson RS (2014). HIF transcription factors, inflammation, and immunity. Immunity, 41:518-528.
De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L,et al. (2009). Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J, 28:3341-3352.
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.
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.
Lopez-Rovira T, Chalaux E, Rosa JL, Bartrons R, Ventura F (2000). Interaction and functional cooperation of NF-κB with Smads. Transcriptional regulation of the junB promoter. J Biol Chem, 275:28937-28946.
Lan HY, Chung AC (2012). TGF-β/Smad signaling in kidney disease. Semin Nephrol, 32:236-243.
Zhao L, Zhang Y, Gao Y, Geng P, Lu Y, Liu X,et al. (2015). JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein. Cell Death Differ, 22:1630-1640.
Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B,et al. (2007). Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest, 117:3810-3820.
Haase VH (2009). Oxygen regulates epithelial-to-mesenchymal transition: insights into molecular mechanisms and relevance to disease. Kidney Int, 76:492-499.
Nieto MA (2011). The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol, 27:347-376.
Higgins DF, Kimura K, Iwano M, Haase VH (2008). Hypoxia-inducible factor signaling in the development of tissue fibrosis. Cell Cycle, 7:1128-1132.
Pohlers D, Brenmoehl J, Löffler I, Müller CK, Leipner C, Schultze-Mosgau S,et al. (2009). TGF-β and fibrosis in different organs - molecular pathway imprints. Biochim Biophys Acta, 1792:746-756.
Wu CY, Tsai YP, Wu MZ, Teng SC, Wu KJ (2012). Epigenetic reprogramming and post-transcriptional regulation during the epithelial-mesenchymal transition. Trends Genet, 28:454-463.
Stadler SC, Allis CD (2012). Linking epithelial-to-mesenchymal-transition and epigenetic modifications. Semin Cancer Biol, 22:404-410.