Correlation of DNA methylation patterns to the phenotypic features of Tibetan elite alpinists in extreme hypoxia

Zhuoma Basang; Shixuan Zhang; La Yang; Deji Quzong; Yi Li; Yanyun Ma; Meng Hao; WeiLin Pu; Xiaoyu Liu; Hongjun Xie; Meng Liang; Jiucun Wang; Qiangba Danzeng

doi:10.1016/j.jgg.2021.05.015

Volume 48 Issue 10

Oct. 2021

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Article Navigation > Journal of Genetics and Genomics > 2021 > 48(10): 928-935

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Correlation of DNA methylation patterns to the phenotypic features of Tibetan elite alpinists in extreme hypoxia

doi: 10.1016/j.jgg.2021.05.015

a. High Altitude Medical Research Center of Tibet University/Center of Tibetan Studies (Everest Research Institute), Tibet University, 10 East Zangda Road, Lhasa, Tibet 850000, China;
b. State Key Laboratory of Genetic Engineering, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai 200438, China;
c. Institute for Six-sector Economy, Fudan University, Shanghai 200433, China;
d. Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai 200438, China;
e. Tibet University-Fudan University Joint Laboratory for Biodiversity and Global Change, Tibet University, 10 East Zangda Road, Lhasa, Tibet 850000, China

Funds:

[2019] No. 1-19

We are most grateful to all the individuals who participated in this study, especially the Chinese Tibet Mountaineering Team, for their contributions to this study. This work was supported by grants from: The Science and Technology Department of Tibet (08080002), 2019 School-level Cultivation Project of Tibet University (ZDTSJH19-08), and the Special Funds from the Central Finance to Support the Development of Local Universities (ZFYJY201902011. Index of Tibetan Finance and Education [2018] No. 54

[2020] No.79). This work was also supported by the Postdoctoral Science Foundation of China (2018M640333), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), Science and Technology Committee of Shanghai Municipality (18490750300), and Major Project of Special Development Funds of Zhangjiang National Independent Innovation Demonstration Zone (ZJ2019-ZD-004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Received Date: 2020-11-02
Accepted Date: 2021-05-30
Rev Recd Date: 2021-05-20
Publish Date: 2021-07-06

Abstract

Abstract

High altitude is an extreme environment that imposes hypoxic pressure on physiological processes, and natives living at high altitudes are more adaptive in certain physiological processes. So far, epigenetic modifications under extreme changes in hypoxic pressures are relatively less understood. Here, we recruit 32 Tibetan elite alpinists (TEAs), who have successfully mounted Everest (8848 m) at least five times. Blood samples and physiological phenotypes of TEAs and 32 matched non-alpinist Tibetan volunteers (non-TEAs) are collected for analysis. Genome-wide DNA methylation analysis identifies 23,202 differentially methylated CpGs (P_adj <0.05, |β| >0.1) between the two groups. Some differentially methylated CpGs are in hypoxia-related genes such as PPP1R13L, MAP3K7CL, SEPTI-9, and CUL2. In addition, Gene ontology enrichment analysis reveals several inflammation-related pathways. Phenotypic analysis indicates that 12 phenotypes are significantly different between the two groups. In particular, TEAs exhibit higher blood oxygen saturation levels and lower neutrophil count, platelet count, and heart rate. For DNA methylation association analysis, we find that two CpGs (cg16687447, cg06947206) upstream of PTEN were associated with platelet count. In conclusion, extreme hypoxia exposure leads to epigenetic modifications and phenotypic alterations of TEA, providing us clues for exploring the molecular mechanism underlying changes under extreme hypoxia conditions.
- Adaptive potentials,
- Extreme hypoxia environment,
- DNA methylation,
- Phenotype association,
- Elite alpinists,
- Mountaineering

These authors contributed equally to this work.

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References

Alkorta-Aranburu, G., Beall, C.M., Witonsky, D.B., Gebremedhin, A., Pritchard, J.K., Di, R.A., 2012. The genetic architecture of adaptations to high altitude in Ethiopia. PLoS Genet. 8, 1003110.

Beall, C.M., 2000. Tibetan and andean patterns of adaptation to high-altitude hypoxia. Hum. Biol. 72, 201-228.

Beall, C.M., 2004. Andean, Tibetan and ethiopian patterns of human adaptation to high-altitude hypoxia. Integr. Comp. Biol. 46, 18-24.

Birks, J.W., Klassen, L.W., Gurney, C.W., 1975. Hypoxia-induced thrombocytopenia in mice. J. Lab. Clin. Med. 86, 230-238.

Cheng, W., Liu, C.H., Hsu, J.P., Chen, J.C., 2002. Effect of hypoxia on the immune response of giant freshwater prawn macrobrachium rosenbergii and its susceptibility to pathogen enterococcus. Fish Shellfish Immunol. 13, 351-365.

Childebayeva, A., Harman, T., Weinstein, J., Goodrich, J.M., Dolinoy, D.C., Day, T.A., Bigham, A.W., Brutsaert, T.D., 2019. DNA methylation changes are associated with an incremental ascent to high altitude. Front. Genet. 10, 1062.

Childebayeva, A., Jones, T.R., Goodrich, J.M., Leon-Velarde, F., Rivera-Chira, M., Kiyamu, M., Brutsaert, T.D., Dolinoy, D.C., Bigham, A.W., 2018. LINE-1 and EPAS1 DNA methylation associations with high-altitude exposure. Epigenetics 14, 1-15.

Ding, M., Van, D., Vellanki, R.N., Foltz, W.D., Mckee, T.D., Sonenberg, N., Pandolfi, P.P., Koritzinsky, M., Wouters, B.G., 2018. The mTOR targets 4E-BP1/2 restrain tumor growth and promote hypoxia tolerance in PTEN-driven prostate cancer. Mol. Cancer Res. 16, 682-695.

Eliasz, S., Liang, S., Chen, Y., De-Marco, M.A., Machek, O., Skucha, S., Miele, L., Bocchetta, M., 2010. Notch-1 stimulates survival of lung adenocarcinoma cells during hypoxia by activating the IGF-1R pathway. Oncogene 29, 2488-2498.

Feng, L., Chen, Q., Zhu, Y., 2016. Research on the biological relationship between methylation of tumor suppressor gene PTEN and gastric cancer. China Health Standard Management. China Health Stand. Manag. 7, 164-165.

Hu, F., Shi, L., Mu, R., Zhu, J., Li, Y., Ma, X., Li, C., Jia, R., Yang, D., Li, Y., Li, Z., 2013. Correction: hypoxia-inducible factor-1α and interleukin 33 form a regulatory circuit to perpetuate the inflammation in rheumatoid arthritis. PLoS One 8, 72650.

Jayasri, N., Semenza, G.L., Prabhakar, N.R., 2017. Epigenetic changes by DNA methylation in chronic and intermittent hypoxia. Am. J. Physiol. Lung Cell Mol. Physiol. 313, 1096.

Julian, C.G., 2017. Epigenomics and human adaptation to high altitude. J. Appl. Physiol. 123, 1362-1370.

Karna, E., Szoka, L., Palka, J., 2012. Thrombin-dependent modulation of β1-integrinmediated signaling up-regulates prolidase and HIF-1α through P-FAK in colorectal cancer cells. Mol. Cell. Biochem. 361, 235-241.

Leek, R.D., Talks, K.L., Pezzella, F., Turley, H., Campo, L., Brown, N.S., Bicknell, R., Taylor, M., Gatter, K.C., Harris, A.L., 2002. Relation of hypoxia-inducible factor-2α (HIF-2α) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in human breast cancer. Cancer Res 62, 1326-1329.

Lira, V.A., Benton, C.R., Yan, Z., Bonen, A., 2010. PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 299, 145-161.

Louis, N.A., Hamilton, K.E., Kong, T., Colgan, S.P., 2005. HIF-dependent induction of apical CD55 coordinates epithelial clearance of neutrophils. FASEB. J. 19, 950-959.

Louis, N.A., Hamilton, K.E., Kong, T., Colgan, S.P., 2013. HIF-dependent induction of apical CD55 coordinates epithelial clearance of neutrophils. FASEB. J. 19, 950-959.

Lu, D., Lou, H., Yuan, K., Wang, X., Wang, Y., Zhang, C., Lu, Y., Yang, X., Deng, L., Zhou, Y., et al., 2016. Ancestral origins and genetic history of Tibetan highlanders. Am. J. Hum. Genet. 99, 580-594.

Maeda, Y., Suzuki, T., Pan, X., Chen, G., Pan, S., Bartman, T., Whitsett, J.A., 2008. Cul2 is required for the activity of hypoxia-inducible factor and vasculogenesis. J. Biol. Chem. 283, 16084-16092.

Mansell, G., Gorrie-Stone, T.J., Bao, Y., Kumari, M., Schalkwyk, L.S., Mill, J., Hannon, E., 2019. Guidance for DNA methylation studies: statistical insights from the illumina epic array. BMC Genom. 20, 366-366.

Moreno, M., Fernández, V., Monllau, J.M., Borrell, V., Lerin, C., Iglesia, N., 2015. Transcriptional profiling of hypoxic neural stem cells identifies calcineurinNFATc4 signaling as a major regulator of neural stem cell biology. Stem. Cell Rep. 5, 157-165.

Morris, T.J., Butcher, L.M., Feber, A., Teschendorff, A.E., Chakravarthy, A.R., Wojdacz, T.K., Beck, S., 2014. ChAMP: 450k chip analysis methylation pipeline. Bioinformatics 30, 428-430.

Mueller, S., Phillips, J., Onar-Thomas, A., Romero, E., Zheng, S., Wiencke, J.K., McBride, S.M., Cowdrey, C., Prados, M.D., Weiss, W.A., Berger, M.S., Gupta, N., Haas-Kogan, D.A., 2012. PTEN promoter methylation and activation of the PI3K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome. Neuro Oncol. 14, 1146-1152.

Palazon, A., Goldrath, A.W., Nizet, V., Johnson, R.S., 2014. HIF transcription factors, inflammation, and immunity. Immunity 41, 518-528.

Peters, M.J., Dixon, G., Kotowicz, K.T., Hatch, D.J., Heyderman, R.S., Klein, N.J., 1999. Circulating platelet-neutrophil complexes represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis and intracellular killing. Br. J. Haematol. 106, 391-399.

Rawłuszko-Wieczorek, A.A., Horbacka, K., Krokowicz, P., Misztal, M., Jagodziński, P.P., 2014. Prognostic potential of DNA methylation and transcript levels of HIF1A and EPAS1 in colorectal cancer. Mol. Cancer Res. 12, 1112-1127.

Sharma, P., Bansal, A., Sharma, P.C., 2015. RNA-seq-based transcriptome profiling reveals differential gene expression in the lungs of sprague-dawley rats during early-phase acute hypobaric hypoxia. Mol. Genet. Genom. 290, 2225-2240.

Simonson, T.S., Yang, Y., Huff, C.D., Yun, H., Qin, G., Witherspoon, D.J., Bai, Z., Lorenzo, F.R., Xing, J., Jorde, L.B., Prchal, J.T., Ge, R., 2010. Genetic evidence for high-altitude adaptation in tibet. Science 329, 72-75.

Takeyama, K., Dabbagh, K., Jeong Shim, J., Dao-Pick, T., Ueki, I.F., Nadel, J.A., 2000. Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: Role of neutrophils. J. Immunol. 164, 1546-1552.

Tazat, K., Schindler, S., Deppeing, R., Mabjeesh, N.J., 2018. Septin 9 isoform 1(SEPT9_i1) specifically interacts with importin-α7 to drive hypoxia-inducible factor(HIF)-1a nuclear translocation. Cytoskeleton (Hoboken) 76, 123-130.

Tian, Z.H., Yuan, C., Yang, K., Gao, X.L., 2019. Systematic identification of key genes and pathways in clear cell renal cell carcinoma on bioinformatics analysis. Ann. Transl. Med. 7, 89.

Uchimaru, J., Matsuo, K., Naito, H., Katamoto, S., Nagatomi, R., 2006. Intermittent normobaric hypoxia induces transient neutrophilia in sedentary subjects but not in trained athletes. Med. Sci. Sports Exerc. 38, 905.

Voisin, S., Eynon, N., Yan, X., Bishop, D.J., 2015. Exercise training and DNA methylation in humans. Acta Physiol. (Oxf) 213, 39-59.

Wang, L., Qiu, J.G., He, J., Liu, W.J., Ge, X., Zhou, F.M., Huang, Y.X., Jiang, B.H., Liu, L.Z., 2019. Suppression of MIR-143 contributes to overexpression of IL-6, HIF-1α and NF-κB p65 in Cr(VI)-induced human exposure and tumor growth. Toxicol. Appl. Pharmacol. 378, 114603.

Wen, Z., Pan, T., Yang, S., Liu, J., Tao, H., Zhao, Y., Xu, D., Shao, W., Wu, J., Liu, X., Wang, Y., Mao, J., Zhu, Y., 2017. Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting ROR β. Mol. Cancer 16, 20.

Wilmshurst, P., 1998. Diving and oxygen. BMJ 317, 996-999.

Xu, S., Li, S., Yang, Y., Tan, J., Lou, H., Jin, W., Yang, L., Pan, X., Wang, J., Shen, Y., Wu, B., Wang, H., Jin, L., 2011. A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol. Biol. Evol. 28, 1003-1011.

Xu, X.H., Huang, X.W., Qun, L., Li, Y.N., Wang, Y., Liu, C., Ma, Y., Liu, Q.M., Sun, K., Qian, F., Jin, L., Wang, J., 2014. Two functional loci in the promoter of EPAS1 gene involved in high-altitude adaptation of Tibetans. Sci. Rep. 4, 7465.

Yu, G., Wang, L.G., Han, Y., He, Q.Y., 2012. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284-287.

Zarate, A., Saucedo, R., Valencia, J., Manuel, L., Hernandez, M., 2014. Early disturbed placental ischemia and hypoxia creates immune alteration and vascular disorder causing preeclampsia. Arch. Med. Res. 45, 519-524.

Zarbock, A., Polanowska-Grabowska, R.K., Ley, K., 2014. Review platelet-neutrophilinteractions: linking hemostasis and inflammation. Blood Rev. 21, 99-111.

Zeng, N., Li, Y., He, L., Xu, X., Galicia, V., Deng, C., Stiles, B.L., 2011. Adaptive basal phosphorylation of eIF2α is responsible for resistance to cellular stress-induced cell death in Pten-null hepatocytes. Mol. Cancer Res. 9, 1708-1717.

Zhang, J.F., Dennell, R., 2018. The last of Asia conquered by Homo sapiens. Science 362, 992-993.

Zhang, Q., Wang, D., Singh, N.K., Kundumani-Sridharan, V., Gadiparthi, L., Rao, C.M., Rao, G.N., 2011. Activation of cytosolic phospholipase A2 downstream of the Src-phospholipase D1 (PLD1)-protein kinase Cγ (PKCγ) signaling axis is required for hypoxia-induced pathological retinal angiogenesis. J. Biol. Chem. 286, 22489-22498.

Zhou, Ming-Ming, 2015. Histone recognition methyl-lysine recognition by ankyrinrepeat proteins. Histone Recogn. 5, 101-124.

Zhuang, J., Droma, T., Sun, S., Janes, C., Mccullough, R.E., Mccullough, R.G., Cymerman, A., Huang, S.Y., Reeves, J.T., Moore, L.G., 1993. Hypoxic ventilatory responsiveness in Tibetan compared with han residents of 3,658 m. J. Appl. Physiol. 74, 303-311.

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