Changes in DNA methylation patterns during high-altitude acclimatization

Abstract

High altitude is a physiologically stressful environment, in part due to reduced atmospheric oxygen pressure leading to hypoxemia. While the physiological changes that occur during acclimatization to high altitude are well characterized, it is unknown what role epigenetic gene regulation may play in these processes. Therefore, the objective of this study was to measure global changes in DNA methylation in response to acute high-altitude exposure, as well as changes in key hypoxia-inducible factor (HIF) pathway genes including EPAS1[E1] (HIF-2α) and EGLN1 (PHD2). Previous studies suggest that EPAS1 and EGLN1 may play key roles in high-altitude adaptation by promoting erythropoiesis, angiogenesis, and modulating metabolic pathways. We hypothesized that acute high-altitude exposure would produce global hypomethylation, as well as increased methylation of the EGLN1 promoter region and decreased methylation of the EPAS1 promoter region, resulting in increased expression of HIF-2α and increased HIF-pathway activation. To test this hypothesis, 15 (5 women, 10 men) healthy participants of sea-level ancestry were recruited (age = 25 ± 4.8). DNA was isolated from venous blood samples which were collected during fasting at sea level and over the course of three days of acclimatization to 3800 m elevation at Barcroft Station (Bishop, CA). DNA methylation levels were measured at CpG sites across the genome using the Illumina Infinium MethylationEPIC chip, and local DNA methylation for EPAS1 and EGLN1 was obtained using a high-resolution melt technique. We identified several CpG sites throughout the genome that were differentially methylated during high-altitude exposure. The top gene ontology terms for differentially methylated sites include bone cell development, DNA damage repair pathways related to p53, and myeloid cell development. There were also significant decreases in CpG sites within HIF-pathway genes such as CD44 and FOXP1. Finally, DNA methylation levels within EPAS1 and EGLN1 changed significantly throughout the process of high-altitude acclimatization, with methylation levels increasing in some regions and decreasing in others. In conclusion, high-altitude exposure leads to complex changes in DNA methylation patterns throughout the genome. These changes likely play a key role in acclimatization and adaptation to chronic hypoxia and future studies will explore these mechanisms. This work has implications for understanding the role of epigenetics in diseases associated with hypoxia such as COPD, COVID-19, sleep apnea, and reproductive diseases such as preeclampsia and endometriosis. This work was funded by a UCR Regent's Faculty Fellowship to ECH and by the UCR School of Medicine. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.