Chromatin as an oxygen sensor and active player in the hypoxia response

Abstract

Changes in the availability or demand for oxygen induce dramatic changes at the cellular level. Primarily, activation of a family of oxygen labile transcription factors, Hypoxia Inducible Factor (HIF), initiates a variety of cellular processes required to re-instate oxygen homeostasis. Oxygen is sensed by molecular dioxygenases in cells, such as the prolyl-hydroxylases (PHDs), enzymes which are responsible for the oxygen-dependent regulation of HIF. As HIF is a transcription factor it must bind DNA sequences of its target genes possibly in the context of a complex chromatin structure. How chromatin structure changes in response to hypoxia is currently unknown. However, the identification of a novel class of histone demethylases as true dioxygenases suggests that chromatin can act as an oxygen sensor and plays an active role in the coordination of the cellular response to hypoxia. This review will discuss the current knowledge on how hypoxia engages with different proteins involved in chromatin organisation and dynamics.

Fig. 1

The HIF degradation pathway. In normoxia the hydroxylases (PHDs and FIH) use O₂ to hydroxylate HIF-1α in the Oxygen Dependent Degradation Domain (ODDD) and the C-Terminal Activation Domain (CTAD). Hydroxylation in the ODDD targets HIF-1α for ubiquitination by the VHL containing E3 ligase complex and HIF-1α is then degraded by the proteasome. In moderate hypoxia the PHDs are inhibited causing HIF-1α accumulation and its dimerisation with HIF-1β. Further decreases in oxygen cause FIH inhibition and subsequent interaction of the HIF-1α-CTAD with co-activators such as p300/CBP.

Fig. 2

HIF induced transcriptional target and cellular pathways. HIF transcriptional targets are very diverse, involving many aspects of cellular regulation. It is the differential regulation of these HIF target genes that allows for the diverse role of HIF, as well as, the integration of a wide variety of other cellular signals.

Fig. 3

Human ATP dependent chromatin remodellers. The identity of chromatin remodelling complexes is defined by the ATPase subunit, which are in turn defined by their unique structure. All the ATPases shown here contain an ATPase domain (DExx and HELICc with an insertion between them (grey)). Switch/Sucrose non fermentable (SWI/SNF) are characterised by an acetylated histone binding bromodomain. ISWI (Imitation Switch) contain SANT/SLIDE domains. CHD/Mi-2 (chromodomain helicase DNA-binding) contains tandem chromodomains that bind methylated lysine 4 in the histone H3 tail. INO80 are characterised by a larger insertion between the DExx and the HELICc regions. Helicase-SANT domains (HSA) are present in SWI/SNF and INO80. In humans there are multiple isoforms of each SNF2 family member that belong to an even more diverse set of ATPase complexes.

Fig. 4

Human ATPase Complexes and their composition. The ATPase subunits SWI/SNF, ISWI, CHD and INO80 form the catalytic centre to a wide variety of chromatin remodelling complexes. The association of the non-catalytic subunits is thought to drive the specificity of the chromatin remodelling complexes. The catalytic subunit is indicated in bold.

Fig. 5

Hypoxia and chromatin crosstalk. Many aspects of chromatin regulation are involved in the modulation of HIF target genes in hypoxia. HIF recruits co-activators such as p300/CBP and depends on histone de-acetylases HDACs for activation, as well as, repression. ATP dependent chromatin remodellers such as SWI/SNF are involved in the regulation of HIF and HIF target genes, however, very little information exists for the roles of the other chromatin remodellers and to what extent HIF may interact/recruit them directly. Histone methylation is an emerging area of hypoxia research as the JmjC de-methylases depend on oxygen for their activity. Furthermore, the majority of the 28 human JmjC proteins are transcriptionally up-regulated by HIF. (−/+) indicates the known effects on transcription.