Abstract
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.
Highlights
Ever since the Cambrian period, oxygen availability has been in the center of energy metabolism and exposure to hypoxia or ischemia can jeopardize the maintenance of tissue homeostasis
The hypoxia response is induced by the oxygen-dependent control of prolyl 4-hydroxylases (PHD1-3), which regulate the cellular expression of hypoxia-inducible transcription factors (HIF1-3) [1,2,3]
Given that gene silencing by polycomb complexes and heterochromatin loci are dependent on trimethylation of H3K9 and H3K27 sites, it implies that the activation of KDM4 and KDM6 demethylases might induce changes in chromatin landscape with aging
Summary
Ever since the Cambrian period, oxygen availability has been in the center of energy metabolism and exposure to hypoxia or ischemia can jeopardize the maintenance of tissue homeostasis. The stabilization of HIF-1α increases the expression of several histone lysine demethylases (KDM), which are crucial enzymes in the control of gene expression in hypoxia but in collaboration with other chromatin modifiers they can affect heterochromatin structures, genome stability, and reprogramming of cellular senescence loci (see below). Beyer et al [86] demonstrated that hypoxia stimulated the HIF-1αdependent expression of KDM3A and KDM4B mRNAs and proteins in cultured cells (Table 1).
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