Human high-altitude adaptation: forward genetics meets the HIF pathway

Bigham, Abigail W.; Lee, Frank S.

doi:10.1101/gad.250167.114

Cited by 263 publications

(313 citation statements)

References 184 publications

(224 reference statements)

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“…The present data, therefore, suggest that Tibetan PHD2 is likely to be a loss-of-function allele that in turn may be a critical component of their remarkable adaptation to chronic hypoxia (56). It must be noted, though, that the Tibetan D4E/C127S allele and the C36S/C42S allele reported here are unlikely to be identical.…”

Section: Discussioncontrasting

confidence: 52%

The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α

Arsenault

Song

Chung

et al. 2016

Molecular and Cellular Biology

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bProlyl hydroxylase domain protein 2 (PHD2) (also known as EGLN1) is a key oxygen sensor in mammals that posttranslationally modifies hypoxia-inducible factor ␣ (HIF-␣) and targets it for degradation. In addition to its catalytic domain, PHD2 contains an evolutionarily conserved zinc finger domain, which we have previously proposed recruits PHD2 to the HSP90 pathway to promote HIF-␣ hydroxylation. Here, we provide evidence that this recruitment is critical both in vitro and in vivo. We show that in vitro, the zinc finger can function as an autonomous recruitment domain to facilitate interaction with HIF-␣. In vivo, ablation of zinc finger function by a C36S/C42S Egln1 knock-in mutation results in upregulation of the erythropoietin gene, erythrocytosis, and augmented hypoxic ventilatory response, all hallmarks of Egln1 loss of function and HIF stabilization. Hence, the zinc finger ordinarily performs a critical positive regulatory function. Intriguingly, the function of this zinc finger is impaired in high-altitude-adapted Tibetans, suggesting that their adaptation to high altitude may, in part, be due to a loss-offunction EGLN1 allele. Thus, these findings have important implications for understanding both the molecular mechanism of the hypoxic response and human adaptation to high altitude.T he hypoxia-inducible factor (HIF) pathway is the primary mediator of the transcriptional response to low oxygen (1-3). In this pathway, prolyl hydroxylase domain protein (PHD) site-specifically prolyl hydroxylates hypoxia-inducible factor ␣ (HIF-␣), thereby providing a recognition motif for the von Hippel-Lindau (VHL) protein, which then promotes the ubiquitination and degradation of HIF-␣ (4-6). Under hypoxic conditions, this modification is arrested, leading to the stabilization of HIF-␣, its dimerization with HIF-␤, and the subsequent activation of a transcriptional program that promotes hypoxic adaptation at the organismal and cellular levels (7, 8). There are two main HIF-␣ paralogues, HIF-1␣ and HIF-2␣, which have overlapping and distinct roles. For example, HIF-1␣ promotes glycolysis, whereas HIF-2␣ (also known as EPAS1) regulates the erythropoietin (EPO) gene.In mammals, there are three PHD paralogues (9, 10), and PHD2 has emerged as a particularly important one. For example, knockout of murine Egln1 but not of Egln2 (Phd1) or Egln3 (Phd2) leads to embryonic lethality (11). In humans, heterozygous lossof-function mutations in the EGLN1 gene that impair catalytic activity are a cause of erythrocytosis (12). In mice, acute global deletion of Egln1 leads to marked erythrocytosis (13, 14). Intriguingly, heterozygous loss of Phd2 function in mice leads to increased respiration (15, 16), and importantly, this phenotype is not observed in either Egln2 Ϫ/Ϫ or Egln3 Ϫ/Ϫ mice (15). PHD2 is closely related to the single ancestral PHD that is present in simple metazoans, such as Trichoplax adhaerens (17). This orthologue shares, in addition to a C-terminal prolyl hydroxylase domain, an N-terminal zinc finger that is absent in b...

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Section: Discussioncontrasting

confidence: 52%

The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α

Arsenault

Song

Chung

et al. 2016

Molecular and Cellular Biology

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“…Our data clearly demonstrate that polycythemia was not required for the development of HIF-2-induced pulmonary hypertension. The fact that HIF-2-induced erythrocytosis does not always associate with pulmonary hypertension, e.g., in humans and mice heterozygous for certain Phd2 mutations (39,41), is likely due to tissue-specific differences in the regulation of HIF-2␣ stability or sensitivity to small increases in HIF-2 transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

“…Bars represent mean values Ϯ SEM. *, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.001. for humans with inherited erythrocytosis due to HIF-2 gain-offunction mutations or nontumorigenic VHL mutations (Chuvash polycythemia) (7,(39)(40)(41). Mice homozygous for the VHL-Chuvash mutation (R200W) spontaneously developed pulmonary hypertension and RVH in a HIF-2-dependent manner (42), a phenotype that was also recapitulated in transgenic mice that carried a HIF-2␣ gain-of-function mutation (G536W) (43).…”

Section: Discussionmentioning

confidence: 99%

The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice

Kapitsinou

Rajendran

Astleford

et al. 2016

Molecular and Cellular Biology

117

138

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f Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (ϳ118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF-2␣ but not HIF-1␣. Furthermore, endothelial HIF-2␣ was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension.

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“…The Tibetan Plateau has an average altitude of some 4,500 m. Humans were first present on the plateau ∼30,000 y ago, with the earliest permanent settlements appearing 6,000-9,000 y ago (4), a period sufficient to drive the natural selection of genetic variants (and associated features) favoring survival and performance in sustained hypoxia (5,6). Evidence supports the selection of genetic variants encoding components of the HIF pathway, such as EPAS1 (encoding HIF-2α) (7) and EGLN1 [prolyl-hydroxylase-2 (PHD2)] (8) in Tibetan populations.…”

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confidence: 99%

Metabolic basis to Sherpa altitude adaptation

Horscroft

Kotwica

Laner

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

179

219

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The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature. metabolism | altitude | skeletal muscle | hypoxia | mitochondria

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Human high-altitude adaptation: forward genetics meets the HIF pathway

Cited by 263 publications

References 184 publications

The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α

The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α

The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice

Metabolic basis to Sherpa altitude adaptation

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