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Tibetan PHD2, an allele with loss-of-function properties.

ABSTRACT: Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway, PHD2 and HIF2A The product of the former induces the degradation of the product of the latter. Key issues regarding Tibetan PHD2 are whether it is a gain-of-function or loss-of-function allele, and how it might contribute to high-altitude adaptation. Tibetan PHD2 possesses two amino acid changes, D4E and C127S. We previously showed that in vitro, Tibetan PHD2 is defective in its interaction with p23, a cochaperone of the HSP90 pathway, and we proposed that Tibetan PHD2 is a loss-of-function allele. Here, we report that additional PHD2 mutations at or near Asp-4 or Cys-127 impair interaction with p23 in vitro. We find that mice with the Tibetan Phd2 allele display augmented hypoxic ventilatory response, supporting this loss-of-function proposal. This is phenocopied by mice with a mutation in p23 that abrogates the PHD2:p23 interaction. Hif2a haploinsufficiency, but not the Tibetan Phd2 allele, ameliorates hypoxia-induced increases in right ventricular systolic pressure. The Tibetan Phd2 allele is not associated with hemoglobin levels in mice. We propose that Tibetans possess genetic alterations that both activate and inhibit selective outputs of the HIF pathway to facilitate successful adaptation to the chronic hypoxia of high altitude.

SUBMITTER: Song D

PROVIDER: S-EPMC7275716 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Tibetan PHD2, an allele with loss-of-function properties.

Song Daisheng D Navalsky Bradleigh E BE Guan Wei W Ingersoll Cassandra C Wang Tao T Loro Emanuele E Eeles Lydia L Matchett Kyle B KB Percy Melanie J MJ Walsby-Tickle John J McCullagh James S O JSO Medina Reinhold J RJ Khurana Tejvir S TS Bigham Abigail W AW Lappin Terence R TR Lee Frank S FS

Proceedings of the National Academy of Sciences of the United States of America 20200515 22

Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway, PHD2 and HIF2A The product of the former induces the degradation of the product of the latter. Key issues regarding Tib ...[more]

PMID: 32414920

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Project description:BackgroundWe have previously described an evolutionarily selected Tibetan prolyl hydroxylase-2 (PHD2D4E;C127S) variant that degrades the hypoxia-inducible factor (HIFα) more efficiently and protects these highlanders from hypoxia-triggered elevation in haemoglobin concentration. High altitude is known to cause acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE) in a section of rapidly ascending non-acclimatised lowlanders. These morbidities are often accompanied by inflammatory response and exposure to hypobaric hypoxia is presumed to be the principal causative agent. We have investigated whether PHD2D4E;C127S variant is associated with prevention of hypoxia-mediated inflammatory milieu in Tibetan highlanders and therefore identify a potential target to regulate inflammation.MethodsWe genotyped the Tibetans using DNA isolated from whole blood. Thereafter immunophenotying was performed on PBMCs from homozygous PHD2D4E;C127S and PHD2WT individuals using flow cytometry. RNA isolated from these individuals was used to evaluate the peripheral level of important transcripts associated with immune as well as hypoxia response employing the nCounter technology. The ex-vivo findings were validated by generating monocytic cell lines (U937 cell line) expressing PHD2D4E;C127S and PHD2WT variants post depletion of endogenous PHD2. We had also collected whole blood samples from healthy travellers and travellers afflicted with AMS and HAPE to evaluate the significance of our ex-vivo and in vitro findings. Hereafter, we also attempted to resolve hypoxia-triggered inflammation in vitro as well as in vivo by augmenting the function of PHD2 using alpha-ketoglutarate (αKG), a co-factor of PHD2.FindingsWe report that homozygous PHD2D4E;C127S highlanders harbour less inflammatory and patrolling monocytes in circulation as compared to Tibetan PHD2WT highlanders. In response to in vitro hypoxia, secretion of IL6 and IL1β from PHD2D4E;C127S monocytes, and their chemotactic response compared to the PHD2WT are compromised, corresponding to the down-modulated expression of related signalling molecules RELA, JUN, STAT1, ATF2 and CXCR4. We verified these functional outcomes in monocytic U937 cell line engineered to express PHD2D4E;C127S and confirmed the down-modulation of the signalling molecules at protein level under hypoxia. In contrast, non-Tibetan sojourners with AMS and HAPE at high altitude (3,600 m above sea level) displayed significant increase in these inflammatory parameters. Our data henceforth underline the role of gain-of-function of PHD2 as the rate limiting factor to harness hyper-activation of monocytes in hypoxic environment. Therefore upon pre-treatment with αKG, we observed diminished inflammatory response of monocytes in vitro and reduction in leukocyte infiltration to the lungs in mice exposed to normobaric hypoxia.InterpretationOur report suggests that gain-of-function PHD2 D4E;C127S variant can therefore protect against inflammation elicited by hypobaric hypoxia. Augmentation of PHD2 activity therefore may be an important method to alleviate inflammatory response to inspired hypoxia.FundingThis study is supported by the Department of Biotechnology, Government of India.

Dataset Information

Tibetan PHD2, an allele with loss-of-function properties.

Publications

Tibetan <i>PHD2</i>, an allele with loss-of-function properties.

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