LINE-1 and EPAS1 DNA methylation associations with high-altitude exposure

Abstract

Recent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1 and LINE-1 repetitive element among 572 Quechua individuals from high-(4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1 DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1 methylation. The number of years lived at high altitude was negatively associated with EPAS1 methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1 rs2236225, TYMS rs502396, FOLH1 rs202676, GLDC rs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1 and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation.

Epigenetics in the public sphere: interdisciplinary perspectives

“…Indeed, one central aspect of the epigenome that fosters a large number of correlative claims is its ability to be highly responsive to environmental changes. Studies have examined a very large number of environmental factors that may be acting via epigenetic means including stress [32], nutrition [33], exercise [34], sleep [35], altitude [36], environmental chemicals [37] and many others. The establishment of correlations has also been facilitated by the equally large number of epigenetic modifications described to date, approximating 500, and including at least three types of DNA methylations (5-methyl cytosine, 5-hydroxy-methyl cytosine and other degradation products, N6-methyl adenosine), 494 types of histone modifications [34], in addition to many non-coding RNAs [35].…”

“…A conflation between correlation and causation in the public sphere is understandable since the scientific literature itself is often fraught with the same issue and only a careful reading of a scientific article can identify whether true causation was demonstrated. For example, the peptide found in soybean, called lunasin, is currently marketed as supporting a ‘healthy epigenetics.’ Lunasin has been shown in in vitro experiments to arrest cell division and induce programmed cell death and prevent carcinogen-induced transformation of mouse skin (fibroblast) cells [36]. In vivo , lunasin also shows potential as its dermal application delays the appearance of tumor and their incidence in a mouse model of skin tumors.…”

Plasma Homocysteine and Polymorphisms of Genes Involved in Folate Metabolism Correlate with DNMT1 Gene Methylation Levels

“…This enhanced expression minimizes uracil misincorporation into the DNA and increases the availability of DNA precursors, such that this polymorphism is often associated with cellular growth and risk of human malignancies, including leukemias, lymphomas, breast cancer, and thoracic neoplasms, among others [40][41][42][43]. Less is known about the contribution of TYMS polymorphisms to the DNA methylation levels, even if the TYMS 28-bp tandem repeat polymorphism was associated with gene-specific methylation levels in the blood DNA of patients systemic lupus erythematosus [44], and other TYMS polymorphisms were linked to either global or gene-specific methylation levels in both healthy and cancerous tissues, reinforcing the evidence that DNA synthesis and methylation are interconnected pathways [17,[45][46][47]. The present findings of a correlation between the TYMS 28-bp tandem repeat polymorphism and DNMT1 promoter methylation levels in blood cells highlight the contribution of this gene to DNA methylation, and suggest that further investigation is warranted in human disorders associated to this variant.…”

DNA Methylation Changes Are Associated With an Incremental Ascent to High Altitude

“…Epigenetic regulation has been studied in the context of high-altitude adaptation in Andeans and Ethiopians (Alkorta-Aranburu et al, 2012; Childebayeva et al, 2019). Despite this, epigenetic changes associated with acclimatization to high-altitude hypoxia are not well understood (Julian et al, 2014).…”

“…We determined the DNA methylation status of the repetitive element LINE-1 and the hypoxia-associated genes EPAS1 , EPO , PPARa , and RXRa . We chose LINE-1 as the marker of global methylation as it has been shown to have different methylation profiles at high compared to low altitude in multigenerational Andeans of Quechua ancestry (Childebayeva et al, 2019). We examined methylation at EPAS1 as polymorphisms near this locus are associated with hemoglobin levels in Tibetans (Beall et al, 2010), EPO as it is involves in red blood cell production (Eckardt et al, 1992; Dame et al, 1998; Beall et al, 2010), and PPARa and RXRa as these hypoxia-associated genes are involved in lipid metabolism regulation (Keller et al, 1993; Chinetti et al, 2000) and PPARA is associated with adaptation in high-altitude populations in the Himalaya (Keller et al, 1993; Chinetti et al, 2000; Simonson et al, 2010; Horscroft et al, 2017).…”