Epigenetics: new questions on the response to hypoxia

Abstract

Reduction in oxygen levels below normal concentrations plays important roles in different normal and pathological conditions, such as development, tumorigenesis, chronic kidney disease and stroke. Organisms exposed to hypoxia trigger changes at both cellular and systemic levels to recover oxygen homeostasis. Most of these processes are mediated by Hypoxia Inducible Factors, HIFs, a family of transcription factors that directly induce the expression of several hundred genes in mammalian cells. Although different aspects of HIF regulation are well known, it is still unclear by which precise mechanism HIFs activate transcription of their target genes. Concomitantly, hypoxia provokes a dramatic decrease of general transcription that seems to rely in part on epigenetic changes through a poorly understood mechanism. In this review we discuss the current knowledge on chromatin changes involved in HIF dependent gene activation, as well as on other epigenetic changes, not necessarily linked to HIF that take place under hypoxic conditions.

Keywords: HIF; chromatin; histone; jumonji; oxygen; stress.

Figure 1

Epigenetic regulation of transcription in response to hypoxia. Schematic representation of the different epigenetic mechanisms involved in the expression of different genes in response to hypoxia. (a) HIF recruits co-activators that enhance gene expression. Upper panel: p300/CBP histone acetyltransferases interact with HIF and acetylate histones in HIF target promoters. HIF-p300/CBP interaction is induced in hypoxia through FIH-1 inhibition. HDAC4, HDAC5 or HDAC7 form a multiprotein complex with HIF-p300 increasing HIF transcriptional activity. HDAC4 and HDAC5 exert their effects by promoting association between HIF and p300. Middle panel: The SWI/SNF complex alters the chromatin structure in some HIF target promoters or enhancers, thereby favoring their expression. Lower panel: Hypoxia promotes changes in the histone methylation status at promoters of hypoxia-inducible genes: Oxygen deprivation activates JMJD1A and inhibits JARID1A histones demethylases, which provoke respectively a decrease in H3K9me2 and an increase in H3K4me2 levels at their target promoters, thus enhancing gene expression. In addition, hypoxia increases H3K4me3 and H3K27me3 levels in some HIF target promoters through an unknown mechanism; (b) Under hypoxia, the interaction between Reptin and HIF1-α is enhanced, leading to recruitment of HDAC1 to some HIF target genes, negatively regulating their transcription; (c) The histone methylation and acetylation status changes in promoters of hypoxia-repressed genes. Hypoxia provokes an increase in H3K9me2 levels as a result of G9a up-regulation. Increased H3K4me3 levels and decreased H3K27me3 and H3K9ac levels have also been observed. Epigenetic events typically associated with transcriptional repression are highlighted in red and those usually associated with transcriptional activation are highlighted in green. Abbreviations: HDAC, Histone Deacetylase; H3, histone H3; me2/3, di/tri-methylated; ac, acetylated.