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Altitude, temperature, circadian rhythms and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Henning Wackerhage, Kenneth A. Dyar, Martin Schönfelder
The second question has been answered by comparing the genome of populations that live at high altitude with the genome of people that live at sea level. The first major breakthrough resulted from a study where the researchers compared the DNA sequence of 50 ethnic Tibetans with that of the closely related Han Chinese. This revealed a 78% frequency difference in one SNP near the EPAS1 gene which encodes the hypoxia-related transcription factor HIF-2α (29). Further studies revealed a whole host of genes with evidence for natural selection of alleles in humans that permanently live at high altitude (Table 11.2).
Genetics and genomics of exposure to high altitude
Published in Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson, Ward, Milledge and West's High Altitude Medicine and Physiology, 2021
Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson
The first three genomic studies to examine genotype-phenotype relationships between adaptive genomic variants and hemoglobin concentration in Tibetans applied these various techniques. Simonson et al. (2010) performed two tests of selection across nearly one million SNPs and identified top genes for adaptation as those that were both contained within a region exhibiting a selective sweep and likely involved in hypoxia sensing and response pathways (Simonson et al. 2010). Ten genes were identified in this overlap and six were related to the HIF system, including EPAS1 and EGLN1, which encode HIF-2α and the oxygen-sensing prolyl hydroxylase PHD2, respectively. EGLN1 and PPARA genes were further associated with relatively lower hemoglobin concentration in Tibetans, and subsequent studies identified associations with metabolic parameters suggesting reduced fatty acid oxidation (Ge et al. 2012) and decreased fatty acid oxidation, greater oxygen utilization, and protection from oxidative stress in skeletal muscle (Horscroft et al. 2017).
High-throughput screening in multicellular spheroids for target discovery in the tumor microenvironment
Published in Expert Opinion on Drug Discovery, 2020
Blaise Calpe, Werner J. Kovacs
Tumor hypoxia and the transcriptional response it induces are instrumental in all key aspects of tumor biology [45], including tumor progression, metastasis [46,47], and resistance to therapy [48]. The hypoxia-inducible factors-1 and −2 alpha (HIF-1α and EPAS1/HIF-2α) are the master regulators of the adaptive response to hypoxia. HIFs form a heterodimer consisting of a constitutively expressed ARNT/HIF-1β subunit and O2-regulated HIF-α subunits. To respond quickly to changes in partial oxygen pressure, HIF-α protein subunits are constantly produced, but under normoxic conditions get hydroxylated on proline subunits [49]. These hydroxylated proline residues on HIF-α serve as recognition motifs for the von Hippel-Lindau tumor suppressor (VHL), leading to HIF-α ubiquitination and subsequent proteasomal degradation [50–52]. In response to hypoxic conditions or loss-of-function of VHL [49], HIF-α prolyl-hydroxylation does not take place anymore, HIF-α transcription factor subunits accumulate quickly and dimerize with ARNT/HIF-1β subunits to induce a profound transcriptional response [7]. HIF transcriptional response leads to the upregulation of hundreds of genes involved in a wide spectrum of pro-oncogenic pathways, including glucose metabolism, angiogenesis, metastasis, and drug resistance. Accordingly, high HIF levels in tumor biopsies were shown to correlate with decreased patient survival in a number of cancer types [53].
Correlation between LincR-Gng2-5′and LincR-Epas1-3′as with the severity of multiple sclerosis in Egyptian patients
Published in International Journal of Neuroscience, 2020
Olfat G. Shaker, Rehab M. Golam, Shymaa Ayoub, Lamiaa I. Daker, Mohamed K. Abd Elguaad, Eman S. Said, Mahmoud A. F. Khalil
The current work supposes that LincR-Gng2-5′ and LincR-Epas1-3′AS share in regulating part of these nearby genes that encode transcription factor regulates expression of cytokines and variable immune regulator so they may have a role in MS pathogenesis [16]. In the present study, there was a significant statistical difference of LincR-Gng in MS patient compared to normal control with upregulation among cases more than twofold change. While LincR-Epas1-3′AS levels were significantly downregulated. These results may be explained by increasing TH1 proinflammatory action (LincR-Gng2-5′ is actively transcribed in TH1 by STAT4 transcription factor) and decrease in the anti-inflammatory TH2 effect (LincR-Epas1-3′AS is actively transcribed in TH2 by STAT6 transcription factor) in multiple sclerosis which is noticed in MS pathology [4, 16].
Therapeutic Perspective of Temozolomide Resistance in Glioblastoma Treatment
Published in Cancer Investigation, 2021
Qin Xia, Liqun Liu, Yang Li, Pei Zhang, Da Han, Lei Dong
Some studies have reported that a hypoxic microenvironment contributes to the formation of GSCs (13). GSCs are a subpopulation of relatively undifferentiated GB cells, which are characterized by self-renewal, unlimited proliferative potential, and multilineage differentiation capacity (14). Hypoxia promotes the sphere formation ability of GSCs and induces the stemness phenotype in non-stem cells, which mainly depends on hypoxia-inducible factors (HIFs) induced signaling pathways (15). The highly expressed hypoxia-inducible factor 1 subunit alpha (HIF1A) and endothelial PAS domain protein 1 (EPAS1) upregulate the expression of stem cell-associated genes, such as PROM1 (also known as CD133, the most widely used and studied marker of GSCs) (16). HIF1A and EPAS1 have different targets and complementary functions in GSC proliferation. HIF1A is responsible for GSC maintenance and inhibits PROM1 (+) cell differentiation, while EPAS1 is specifically involved in enhancing the phenotype of GSCs and increases the ratio of GSCs to non-stem cells (17). EPAS1 expression has been reported to induce neurosphere formation and the expression of stem cell markers in non-stem GB cells, and it increases the tumorigenic potential of non-stem GB cells (15). Moreover, the abundant vascular systems contribute to the maintenance of stemness and activate pathways leading to enrichment in GSCs capable of DNA repair and migration (18). GSCs exhibit enhanced angiogenesis, proliferation, and invasiveness, which confer the cells a carcinogenic phenotype. In addition, due to the self-renewal and multiple differentiation potential, GSCs play a key role in the initiation and progression of GB.