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Aging and disease    2016, Vol. 7 Issue (2) : 180-200     DOI: 10.14336/AD.2015.0929
Review Article |
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
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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.

Keywords Aging      Chromatin      Epigenetic      Hypoxia      Pseudohypoxia      Senescence     
Corresponding Authors: Antero Salminen   
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These authors equally contribute this work

Issue Date: 01 April 2016
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Antero Salminen
Kai Kaarniranta
Anu Kauppinen
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Antero Salminen,Kai Kaarniranta,Anu Kauppinen. Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases[J]. Aging and disease, 2016, 7(2): 180-200.
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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.
KDM3AH3K9me1,2[85-91, 93]
KDM4BH3K9me2,3 &[85-87, 89, 91, 92]
KDM4CH3K9me2,3 &[85, 86, 89]
KDM5BH3K4me2,3[87, 89]
KDM6BH3K27me2,3[89, 95]
Table 1  HIF-1α-inducible histone lysine demethylases (KDMs)
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