Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, m6A modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression. However, we observe that YTHDF1 high expression correlates with better clinical outcome, with its depletion rendering cancerous cells resistant to cisplatin (DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the downstream mediator of YTHDF1. Together, these findings highlight the critical role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.

/pdf/ythdf1-links-hypoxia-adaptation-and-non-small-cell-lung-2ywetjbj34.pdf

YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression.

Variation in O2 transport characteristics among Andean, Tibetan, and, when available, Ethiopian high-altitude residents supports the existence of genetic adaptations that improve the distribution o...

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.00321.2017

Measuring high-altitude adaptation

Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that hypoxia-inducible factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This Review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell-specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure.

/pdf/hypoxia-inducible-factor-signaling-in-pulmonary-hypertension-2c8twwtv1d.pdf

Hypoxia-inducible factor signaling in pulmonary hypertension

High-altitude environments present strong stresses for living organisms, which have driven striking phenotypic and genetic adaptations. While previous studies have revealed multiple genetic adaptations in high-altitude species, how evolutionary history (i.e., phylogenetic background) contributes to similarity in genetic adaptations to high-altitude environments is largely unknown, in particular in a group of birds. We explored this in 3 high-altitude passerine birds from the Qinghai-Tibet Plateau and their low-altitude relatives in lowland eastern China. We generated transcriptomic data for 5 tissues across these species and compared sequence changes and expression shifts between high- and low-altitude pairs. Sequence comparison revealed that similarity in all 3 high-altitude species was high for genes under positive selection (218 genes) but low in amino acid substitutions (only 4 genes sharing identical amino acid substitutions). Expression profiles for all genes identified a tissue-specific expression pattern (i.e., all species clustered by tissue). By contrast, an altitude-related pattern was observed in genes differentially expressed between all 3 species pairs and genes associated with altitude, suggesting that the high-altitude environment may drive similar expression shifts in the 3 high-altitude species. Gene expression level, gene connectivity, and the interactions of these 2 factors with altitude were correlated with evolutionary rates. Our results provide evidence for how gene sequence changes and expression shifts work in a concerted way in a group of high-altitude birds, leading to similar evolution routes in response to high-altitude environmental stresses.

Comparative transcriptomics of 3 high-altitude passerine birds and their low-altitude relatives

Ascent to high altitude is associated with physiological responses that counter the stress of hypobaric hypoxia by increasing oxygen delivery and by altering tissue oxygen utilisation via metabolic modulation. At the cellular level, the transcriptional response to hypoxia is mediated by the hypoxia-inducible factor (HIF) pathway and results in promotion of glycolytic capacity and suppression of oxidative metabolism. In Tibetan highlanders, gene variants encoding components of the HIF pathway have undergone selection and are associated with adaptive phenotypic changes, including suppression of erythropoiesis and increased blood lactate levels. In some highland populations, there has also been a selection of variants in PPARA, encoding peroxisome proliferator-activated receptor alpha (PPARα), a transcriptional regulator of fatty acid metabolism. In one such population, the Sherpas, lower muscle PPARA expression is associated with a decreased capacity for fatty acid oxidation, potentially improving the efficiency of oxygen utilisation. In lowlanders ascending to altitude, a similar suppression of fatty acid oxidation occurs, although the underlying molecular mechanism appears to differ along with the consequences. Unlike lowlanders, Sherpas appear to be protected against oxidative stress and the accumulation of intramuscular lipid intermediates at altitude. Moreover, Sherpas are able to defend muscle ATP and phosphocreatine levels in the face of decreased oxygen delivery, possibly due to suppression of ATP demand pathways. The molecular mechanisms allowing Sherpas to successfully live, work and reproduce at altitude may hold the key to novel therapeutic strategies for the treatment of diseases to which hypoxia is a fundamental contributor.

/pdf/metabolic-adjustment-to-high-altitude-hypoxia-from-genetic-21nxux1t9b.pdf

Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications

Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of EPAS1, a gene encoding hypoxia inducible factor 2α (HIF-2α) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed that the Tibetan-enriched EPAS1 variants down-regulate expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia, mirroring the situation in Tibetans. Furthermore, we found that the Tibetan version of EPAS1 is not only associated with the relatively low hemoglobin level as a polycythemia protectant, but also is associated with a low pulmonary vasoconstriction response in Tibetans. We propose that the down-regulation of EPAS1 contributes to the molecular basis of Tibetans' adaption to high-altitude hypoxia.

Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High-Altitude Hypoxia.

Yak is one of the largest native mammalian species at the Himalayas, the highest plateau area in the world with an average elevation of >4,000 m above the sea level. Yak is well adapted to high altitude environment with a set of physiological features for a more efficient blood flow for oxygen delivery under hypobaric hypoxia. Yet, the genetic mechanism underlying its adaptation remains elusive. We conducted a cross-tissue, cross-altitude, and cross-species study to characterize the transcriptomic landscape of domestic yaks. The generated multi-tissue transcriptomic data greatly improved the current yak genome annotation by identifying tens of thousands novel transcripts. We found that among the eight tested tissues (lung, heart, kidney, liver, spleen, muscle, testis, and brain), lung and heart are two key organs showing adaptive transcriptional changes and >90% of the cross-altitude differentially expressed genes in lung display a nonlinear regulation. Pathways related to cell survival and proliferation are enriched, including PI3K-Akt, HIF-1, focal adhesion, and ECM-receptor interaction. These findings, in combination with the comprehensive transcriptome data set, are valuable to understanding the genetic mechanism of hypoxic adaptation in yak.

Qu Zhang

Papers

Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High-Altitude Hypoxia.

The Transcriptomic Landscape of Yaks Reveals Molecular Pathways for High Altitude Adaptation