O₂
EstablishedMolecular oxygen is a co-substrate, not only a signal
Oxygen is consumed directly by Fe(II)- and 2-oxoglutarate-dependent dioxygenases. Its availability therefore sets the rate of the reactions these enzymes perform.
Related
Hypoxia biology · Interactive figure
The same chemistry
Oxygen is not only a signal. It is a substrate for the enzymes that sense it, that make and break chromatin marks, and that decide which genes a cell can switch on. Move the oxygen dial and watch both pathways respond together.
21%O₂
Sea level · normoxia
PHD 100% · FIH 100% · TET 100% · KDM 100%
Nonlinear scale, expanding the low-oxygen range. Arrow keys adjust; Home and End jump to the extremes.
With oxygen present, the cell actively destroys its own hypoxia signal.
Without enough oxygen, the destruction machinery stalls and HIF survives.
PHD enzymes and FIH are Fe(II)- and 2-oxoglutarate-dependent dioxygenases that use molecular oxygen directly. When oxygen falls, their chemistry slows.
PHD enzymes, TET enzymes and JmjC histone demethylases all belong to the Fe(II)- and 2-oxoglutarate-dependent dioxygenase family. They use molecular oxygen as part of their reactions. When oxygen falls, these enzyme systems are affected in parallel, linking oxygen sensing directly to changes in gene regulation and chromatin.
Transcriptional
Stability, dimerisation and DNA binding
Normoxia — destructionactivestalled
Hypoxia — survival and outputoffactive
Isoform switch and modulation
Epigenomic
DNA and histone marks under the same oxygen dependence
Oxygen-sensitive and HIF-regulated KDMs
Different chemistry
Not every demethylase is an oxygen-dependent dioxygenase.
Context-dependentPseudohypoxia — changes without low oxygen
Mutations in IDH1/2, SDH or FH cause metabolite accumulation that inhibits 2-OG-dependent dioxygenases. Epigenetic changes can therefore occur without hypoxia at all.
Succinate and 2-hydroxyglutarate compete with 2-oxoglutarate, inhibiting TET and JmjC enzymes. This pseudohypoxic state demonstrates the shared chemistry underlying both pathways.
Genes: IDH1, IDH2, SDH, FH
Emerging mechanisms
Labelled Emerging: active areas where causality is still being established.
Both layers are hidden. Enable the transcriptional or epigenomic layer above to view the pathway.
Hotspots respond to the oxygen dial. Selected organs are highlighted across all three views.
Two tracks that overlap but are not identical. Selecting a node highlights it in the Sensor and Body views, and nodes that are not yet engaged at the current oxygen level are dimmed.
secSeconds
2–30 min2–30 minutes
1–4 h1–4 hours
12–48 h12–48 hours
DaysDays
WeeksWeeks
Months–yearsMonths to years
GenerationsGenerations
Transcriptional
—
Epigenomicincl. RNA layer
no major chromatin story yet
—
Separate axis · population adaptation
Evolutionary adaptation is not the next stage of an individual's acclimatisation. It is a distinct process acting over generations.
RNA-level layer
The epigenomic track includes RNA regulation: the hypoxamiR miR-210, hypoxia-responsive long non-coding RNAs such as NEAT1 and MALAT1, and m6A modification. ALKBH5 removes m6A and is itself a 2-OG-dependent dioxygenase.
Reading the tracks
Early transcription (carotid body, HIF stabilisation) precedes measurable chromatin change. Demethylase effects begin within minutes, while DNA methylation and stable chromatin changes emerge over hours to weeks.
Full text and referencesEvery node in this figure, with evidence status and sources
EstablishedContext-dependentEmergingEvidence status, not a ranking.
PHD1/2/3
EstablishedGene EGLN1/2/3
Prolyl hydroxylases gate HIF stability
PHD enzymes hydroxylate proline residues in HIF-1α and HIF-2α. This modification is required for VHL recognition and rapid degradation.
Deeper explanation
PHD2 (EGLN1) is the principal regulator of HIF-1α in most cell types. PHD activity depends on oxygen, Fe(II), ascorbate and 2-oxoglutarate. The relative oxygen sensitivities of PHD1, PHD2 and PHD3 differ between tissues.
Related
FIH
EstablishedGene HIF1AN
Asparaginyl hydroxylation tunes HIF activity
FIH hydroxylates asparagine 803 in HIF-1α, blocking recruitment of the p300/CBP co-activators.
Deeper explanation
Because FIH restrains HIF activity rather than its stability, loss of FIH activity in hypoxia affects which targets are switched on, not simply whether HIF is present.
Related
VHL
EstablishedGene VHL
VHL reads the hydroxyl mark
The von Hippel–Lindau E3 ubiquitin ligase complex recognises hydroxylated HIF-1α and targets it for ubiquitination.
Related
Proteasome
EstablishedRapid destruction keeps HIF low
When oxygen and PHD activity are sufficient, HIF-1α is destroyed within minutes, so transcriptional output stays low.
HIF-1α
EstablishedGene HIF1A
HIF-1α accumulates when hydroxylation fails
As oxygen falls, PHD activity drops. HIF-1α is no longer marked for degradation, so it accumulates in the cytoplasm, translocates to the nucleus and dimerises with ARNT.
Related
HIF-1β / ARNT
EstablishedGene ARNT
The constitutive partner
ARNT is expressed independently of oxygen. The HIF-1α–ARNT heterodimer is the active transcription factor.
HRE
EstablishedA short DNA motif recruits the dimer
The hypoxia response element contains the core sequence 5′-RCGTG-3′. HIF dimers bind HREs in the enhancers and promoters of target genes.
p300 / CBP
EstablishedGenes EP300, CREBBP
Co-activators set transcriptional output
Once bound to DNA, HIF recruits the p300/CBP acetyltransferases, which acetylate chromatin and help assemble the transcriptional machinery.
Related
Transcription
EstablishedAerobic metabolism is re-tuned
HIF drives glycolytic enzymes, angiogenic factors such as VEGF and many other targets, changing how cells use oxygen and nutrients.
HIF-2α
EstablishedGene EPAS1
The chronic partner
HIF-2α shares the PHD–VHL control system but drives a partly distinct programme, including erythropoietin in the kidney. It often dominates the later phase of the response.
HIF-3α
Context-dependentGene HIF3A
Predominantly regulatory
HIF-3α is expressed as multiple splice variants and is best understood as a negative or modulatory regulator of the response rather than a classic activator.
TET1/2/3
EstablishedGenes TET1, TET2, TET3
Oxygen is a substrate for DNA demethylation
TET enzymes are Fe(II)- and 2-oxoglutarate-dependent dioxygenases that oxidise 5-methylcytosine towards 5-hydroxymethylcytosine and further products as part of active DNA demethylation. In hypoxia, reduced TET activity is associated with altered DNA methylation.
Deeper explanation
The DNA methylation response is region-specific. Some loci gain methylation while others lose it, so hypoxic changes should not be described as a uniform global shift.
Related
5mC / 5hmC
Context-dependentMethylation balance shifts
When TET activity falls, 5-methylcytosine is less efficiently oxidised, so 5hmC can decline and methylation patterns can shift. The effect differs between genomic regions rather than being uniform.
Related
JmjC KDMs
EstablishedGenes KDM6A, KDM5A, KDM4A
Histone demethylases are also oxygen-dependent
JmjC-domain histone demethylases use the same Fe(II)/2-OG chemistry as PHD and TET enzymes. Hypoxia causes rapid changes in histone methylation that can in turn influence HIF signalling.
Deeper explanation
Batie and colleagues reported rapid hypoxia-induced changes to histone methylation, while Chakraborty and colleagues showed that KDM6A can sense oxygen directly to control chromatin and cell fate.
Related
H3K4me3 / H3K27me3
Context-dependentRepressive and active marks accumulate
Reduced demethylase activity can cause histone methylation to accumulate. These marks can influence chromatin accessibility and gene expression.
Related
KDM6A / UTX
Context-dependentGene KDM6A
A demethylase that directly senses oxygen
KDM6A can behave as a direct oxygen sensor controlling chromatin state and cell fate, linking oxygen availability to developmental decisions.
KDM5A
Context-dependentGene KDM5A
Sensitive oxygen-dependent regulator
Some JmjC enzymes are proposed to act as unusually sensitive oxygen-dependent regulators of chromatin, adding to the complexity of the response.
LSD1 / KDM1A
EstablishedGene KDM1A
A demethylase with different chemistry
LSD1/KDM1A is not a JmjC demethylase. It is a FAD-dependent amine oxidase that uses a distinct catalytic mechanism and is not directly oxygen-dependent in the same way.
Related
KDM3A / KDM4A
Context-dependentGenes KDM3A, KDM4A
Feedback from HIF to chromatin
Some KDMs, including KDM3A/JMJD1A and KDM4 family members, are themselves HIF target genes. The epigenomic and transcriptional responses therefore feed into one another.
Related
Pseudohypoxia
Context-dependentGenes IDH1, IDH2, SDH, FH
The relationship is chemical, not only transcriptional
Mutations in IDH1/2, SDH or FH cause metabolite accumulation that inhibits 2-OG-dependent dioxygenases. Epigenetic changes can therefore occur without hypoxia at all.
Deeper explanation
Succinate and 2-hydroxyglutarate compete with 2-oxoglutarate, inhibiting TET and JmjC enzymes. This pseudohypoxic state demonstrates the shared chemistry underlying both pathways.
miR-210
EstablishedGene MIR210
The canonical hypoxamiR
miR-210 is a hypoxia-induced microRNA that fine-tunes mitochondrial metabolism by targeting transcripts including ISCU, COX10 and GPD1L.
lncRNAs
Context-dependentGenes NEAT1, MALAT1, HIF1A-AS2
Long non-coding RNA layer
Several long non-coding RNAs are hypoxia-responsive and contribute to chromatin organisation, splicing and the stability of HIF transcripts.
m6A / ALKBH5
Context-dependentGene ALKBH5
Oxygen-sensitive RNA modification
ALKBH5 is a Fe(II)- and 2-OG-dependent dioxygenase that removes the m6A mark from RNA, giving another link between oxygen and gene regulation beyond chromatin.
Histone lactylation
EmergingMetabolite-derived chromatin marks
Lactate produced by increased glycolysis can be deposited as lactyl groups on histones, offering a metabolic route to chromatin regulation in hypoxia.
Acetyl-CoA / acetylation
EmergingMetabolite availability shapes acetylation
Histone acetylation depends on acetyl-CoA availability, which is altered by hypoxic metabolic rewiring. This is an area of active investigation.
Intermittent vs sustained hypoxia
EmergingPattern matters
Repeated cycles of hypoxia and reoxygenation can produce different transcriptional and epigenomic outcomes from sustained hypoxia, and are used experimentally in therapeutic protocols.
Hypoxic memory
EmergingPersistent programming
Developmental or repeated hypoxic exposure may leave lasting chromatin and methylation changes that alter later responses, sometimes described as hypoxic memory or developmental programming.
Carotid body
EstablishedThe first alarm, within seconds
Glomus cells in the carotid body detect falling oxygen and rapidly increase respiratory drive through ion-channel and mitochondrial mechanisms, triggering the ventilatory response.
Lungs
EstablishedThe only vascular bed that constricts
Hypoxic pulmonary vasoconstriction narrows pulmonary arterioles to divert blood towards better-ventilated regions. It is unique among vascular beds, which otherwise dilate when oxygen falls.
Related
HAPE
EstablishedWhen the response turns pathological
Exaggerated and uneven pulmonary vasoconstriction raises capillary pressure and contributes to high-altitude pulmonary oedema, a life-threatening condition.
Brain
EstablishedSwelling and sickness
Cerebral vasodilation, altered vascular permeability and impaired autoregulation contribute to acute mountain sickness and, in severe cases, high-altitude cerebral oedema.
Kidney
EstablishedThe oxygen meter of the blood
Renal interstitial cells sense reduced oxygen and increase erythropoietin production, largely under HIF-2α control, linking oxygen sensing to red cell mass.
Related
Liver / gut
Context-dependentFreeing up iron
Hepcidin suppression during hypoxia increases dietary iron absorption and its release from stores, supporting increased erythropoiesis.
Bone marrow
EstablishedBuilding the oxygen carriers
Rising erythropoietin drives erythroid progenitor expansion and reticulocytosis, gradually raising haemoglobin concentration and oxygen-carrying capacity.
Heart / skeletal muscle
EstablishedRewiring metabolism
HIF targets increase glucose uptake and glycolysis and induce PDK1, which restrains mitochondrial oxygen consumption. Longer-term adaptation includes changes in mitochondrial content and mitophagy.
Immune cells
Context-dependentInflammation gets louder
Hypoxia interacts with inflammatory signalling, including HIF/NF-κB relationships, while extracellular adenosine provides a regulatory counterweight.
Population adaptation
EstablishedGenes EPAS1, EGLN1
Evolution, not acclimatisation
Tibetans carry variants near EPAS1 (HIF-2α) and EGLN1 (PHD2) associated with altered haemoglobin and ventilatory responses; the EPAS1 haplotype shows evidence of Denisovan-like introgression. Andean and Ethiopian highlanders show partly distinct signals.
Deeper explanation
These are population-genetic adaptations that arose over many generations. They are not the next step of an individual's physiological acclimatisation and should be read as a separate axis of the story.
References
- Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annual Review of Pathology. 2014.
- Kaelin WG, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Molecular Cell. 2008.
- Thienpont B, et al.. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature. 2016.
- Batie M, et al.. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science. 2019.
- Chakraborty AA, et al.. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science. 2019.
- Huerta-Sánchez E, et al.. Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature. 2014.
- Bärtsch P, Swenson ER. Acute high-altitude illnesses. New England Journal of Medicine. 2013.
- Sylvester JT, et al.. Hypoxic pulmonary vasoconstriction. Physiological Reviews. 2012.
- Zhang D, et al.. Metabolic regulation of gene expression by histone lactylation. Nature. 2019.
- Jaakkola P, et al.. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001.
- Ivan M, et al.. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001.
- Lando D, et al.. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes & Development. 2002.
- Chan SY, Loscalzo J. MicroRNA-210: a unique and pleiotropic hypoxamir. Cell Cycle. 2010.
- Zheng G, et al.. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Molecular Cell. 2013.