The human blood transcriptome exhibits time-of-day-dependent response to hypoxia: Lessons from the highest city in the world

Manella, Gal; Ezagouri, Saar; Champigneulle, Benoît; Gaucher, Jonathan; Mendelson, Monique; Lemarié, Emeline; Stauffer, Émeric; Pichon, Aurélien; Howe, Connor A.; Doutreleau, Stéphane; Golik, Marina; Vergès, Samuel; Asher, Gad

doi:10.1016/j.celrep.2022.111213

Cited by 15 publications

(10 citation statements)

References 72 publications

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“…In contrast, Manella et al discovered that genes associated with immune response can exhibit differential expression patterns based on both the duration of exposure to high altitude and the specific altitude level (e.g., 3,800 meters in Puno compared to 5,100 meters in La Rinconada). Additionally, the timing of the measurements during the day also plays a role in these gene expression variations (27). The investigation revealed that time-associated gene alterations were linked to innate immunity, specifically pertaining to the activation of neutrophils.…”

Section: Discussionmentioning

confidence: 99%

The effect of altitude on the expression of immune-related genes in Peruvian rural indigenous

Jaramillo-Valverde,

de Araújo,

Poterico

et al. 2024

Preprint

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Background: Some genes associated with immune response have been elucidated in some Andean populations, which may explain part of the immune system adaptation and pathogen response in high-altitude residents. We performed differential expression analysis and mainly focused on genes with high fold-change between groups and those genes with differential expression related to the immune system. Methods: We performed a transcriptome analysis of Peruvian individuals, primarily from rural areas, with high genetic backgrounds from ancient indigenous people, exposed to different living altitudes (high vs low). We collected peripheral blood mononuclear cells (PBMC) from 62 volunteers and exposed them to bacterial lipopolysaccharide (LPS), Pam3CSK4 (a synthetic triacylated lipopeptide responsible for bacterial components), and R848 (an imidazoquinoline compound related to viral nucleic acids). Results: Differential expression analysis results and data integration analysis with immune system pathway data exhibit a set of 17 genes associated with the immune system, nine down-regulated genes (ITGAX, CCL22, CSF1, CXCL8, IL12A, MMP9, CSF2, PTGS2, ENSG00000138685.17), and eight up-regulated genes (HLA-DPB1, FN1, CD36, MMP2, HLA-DRB1, FCGR1A, CCL17, HLA-DRB5). These genes are notably enriched in antigen-presenting cells, such as dendritic cells and macrophages. Conclusion: The differential expression of immune system genes in native inhabitants with a prominent Andean genetic background highlights the active involvement of both the innate and adaptive immune systems. Remarkably, our study revealed a distinct gene expression signature in our population, setting it apart from other transcriptomic studies conducted thus far.

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Section: Discussionmentioning

confidence: 99%

The effect of altitude on the expression of immune-related genes in Peruvian rural indigenous

Jaramillo-Valverde,

de Araújo,

Poterico

et al. 2024

Preprint

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“…Traveling to high altitude can lead to physiological hypoxia for those dwelling at sea level. In a related study, gene expression of the blood was examined for eight healthy participants at both sea level and high altitude (3800 m and 5100 m) [ 24 ]. It was evident that NDG gene expression was generally higher at high altitude compared to that at sea level ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

“…The effect of systemic hypoxia on gene dysregulation was evaluated using four transcriptome datasets, including two RNA-Seq datasets for physiological hypoxia (high altitude-related, GSE164890 and GSE196728) [ 23 , 24 ] and two microarray datasets for pathological hypoxia (stroke-related, GSE36791 and GSE58294) [ 25 , 26 ]. The RNA-Seq datasets were downloaded directly from the corresponding GEO web pages.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia and Activation of Neutrophil Degranulation-Related Genes in the Peripheral Blood of COVID-19 Patients

Lei

2024

Viruses

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Severe COVID-19 is characterized by systematic hyper-inflammation and subsequent damage to various organs. Therefore, it is critical to trace this cascade of hyper-inflammation. Blood transcriptome has been routinely utilized in the interrogation of host immune response in COVID-19 and other infectious conditions. In this study, consensus gene dysregulation in the blood was obtained from 13 independent transcriptome studies on COVID-19. Among the up-regulated genes, the most prominent functional categories were neutrophil degranulation and cell cycle, which is clearly different from the classical activation of interferon signaling pathway in seasonal flu. As for the potential upstream causal factors of the atypical gene dysregulation, systemic hypoxia was further examined because it is much more widely reported in COVID-19 than that in seasonal flu. It was found that both physiological and pathological hypoxia can induce activation of neutrophil degranulation-related genes in the blood. Furthermore, COVID-19 patients with different requirement for oxygen intervention showed distinctive levels of gene expression related to neutrophil degranulation in the whole blood, which was validated in isolated neutrophils. Thus, activation of neutrophil degranulation-related genes in the blood of COVID-19 could be partially attributed to hypoxia. Interestingly, similar pattern was also observed in H1N1 infection (the cause of Spanish flu) and several other severe respiratory viral infections. As for the molecular mechanism, both HIF-dependent and HIF-independent pathways have been examined. Since the activation of neutrophil degranulation-related genes is highly correlated with disease severity in COVID-19, early detection of hypoxia and active intervention may prevent further activation of neutrophil degranulation-related genes and other harmful downstream hyper-inflammation. This common mechanism is applicable to current and future pandemic as well as the severe form of common respiratory infection.

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“…Analysis of human whole blood transcriptome at different altitudes showed that oxygen availability strongly affects the daily variance in gene expression, especially genes involved in immunoregulation. 75 Laboratory experiments evoking intermittent hypoxia in mice, mimicking sleep apnea in humans, resulted in large changes in clock-regulated transcription in a number of tissues, showing tissue-specific patterns of regulation. 76,77 Cardiopulmonary tissues were disproportionately impacted.…”

Section: Oxygen Influences the Molecular Circadian Clockmentioning

confidence: 99%

Circadian Clock and Hypoxia

Sartor,

Ferrero-Bordera,

Haspel

et al. 2024

Circulation Research

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The timing of life on Earth is remarkable: between individuals of the same species, a highly similar temporal pattern is observed, with shared periods of activity and inactivity each day. At the individual level, this means that over the course of a single day, a person alternates between two states. They are either upright, active, and communicative or they lie down in a state of (un)consciousness called sleep where even the characteristic of neuronal signals in the brain shows distinctive properties. The circadian clock governs both of these time stamps—activity and (apparent) inactivity—making them come and go consistently at the same approximate time each day. This behavior thus represents the meeting of two pervasive systems: the circadian clock and metabolism. In this article, we will describe what is known about how the circadian clock anticipates daily changes in oxygen usage, how circadian clock regulation may relate to normal physiology, and to hypoxia and ischemia that can result from pathologies such as myocardial infarction and stroke.

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The human blood transcriptome exhibits time-of-day-dependent response to hypoxia: Lessons from the highest city in the world

Cited by 15 publications

References 72 publications

The effect of altitude on the expression of immune-related genes in Peruvian rural indigenous

The effect of altitude on the expression of immune-related genes in Peruvian rural indigenous

Hypoxia and Activation of Neutrophil Degranulation-Related Genes in the Peripheral Blood of COVID-19 Patients

Circadian Clock and Hypoxia

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