Telomeres are nucleoprotein structures located at the end of each chromosome,which function in terminal protection and genomic stability.Telomeric damage is closely related to replicative senescence in vitro and physi...Telomeres are nucleoprotein structures located at the end of each chromosome,which function in terminal protection and genomic stability.Telomeric damage is closely related to replicative senescence in vitro and physical aging in vivo.As relatively long-lived mammals based on body size,bats display unique telomeric patterns,including the upregulation of genes involved in alternative lengthening of telomeres(ALT),DNA repair,and DNA replication.At present,however,the relevant molecular mechanisms remain unclear.In this study,we performed cross-species comparison and identified EPAS1,a well-defined oxygen response gene,as a key telomeric protector in bat fibroblasts.Bat fibroblasts showed high expression of EPAS1,which enhanced the transcription of shelterin components TRF1 and TRF2,as well as DNA repair factor RAD50,conferring bat fibroblasts with resistance to senescence during long-term consecutive expansion.Based on a human single-cell transcriptome atlas,we found that EPAS1 was predominantly expressed in the human pulmonary endothelial cell subpopulation.Using in vitro-cultured human pulmonary endothelial cells,we confirmed the functional and mechanistic conservation of EPAS1 in telomeric protection between bats and humans.In addition,the EPAS1 agonist M1001 was shown to be a protective compound against bleomycin-induced pulmonary telomeric damage and senescence.In conclusion,we identified a potential mechanism for regulating telomere stability in human pulmonary diseases associated with aging,drawing insights from the longevity of bats.展开更多
AIM: To evaluate the prognostic signif icance of HIF- 2α/EPAS1 expression in hepatocellular carcinoma (HCC). METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 ...AIM: To evaluate the prognostic signif icance of HIF- 2α/EPAS1 expression in hepatocellular carcinoma (HCC). METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 cases of normal liver tissue were investigated by immunohistochemistry (IHC) for HIF-2α/EPAS1 using a standard detection system. Correlations with clinicopathological factors, VEGF, microvessel density (MVD), and prognosis were analyzed. RESULTS: Immunoreactivity of HIF-2α/EPAS1 was positive in 69.5% of HCC, 55.6% of adjacent noncancerous tissue, and 0% of normal liver tissue. And it was significantly correlated with tumor grade, venous invasion, intrahepatic metastasis, necrosis, and capsule infiltration. Correlation analysis of HIF-2α/EPAS1 with angiogenic factor VEGF (P < 0.001), and MVD (P = 0.016) was also noted. HIF-2α/EPAS1 protein was less frequently expressed in low MVD cases, whereas a high rate of expression was noted in cases with both medium and high MVD (P = 0.042). By Kaplan-Meier analysis, strong HIF-2α/EPAS1 staining (> 50% of tumor cells) in HCC correlated with a shortened survival in patients (Cox's regression, P < 0.001, r = 3.699). CONCLUSION: We conclude that HIF-2α/EPAS1 expression may play an important role in tumor progression and prognosis of HCC. Assessment of HIF-2α/EPAS1 expression in HCC may be used as a diagnostic tool and possibly a target in the treatment of HCC.展开更多
Endothelial PAS domain protein 1 gene （EPAS1） is a key transcription factor that activates the expression of oxygen-regu- lated genes. In this study, in order to better understand the effects of EPAS1 gene on hemato...Endothelial PAS domain protein 1 gene （EPAS1） is a key transcription factor that activates the expression of oxygen-regu- lated genes. In this study, in order to better understand the effects of EPAS1 gene on hematologic parameters in yak, we firstly quantified the tissue expression patterns for EPASl mRNA of yak, identified polymorphism in this gene and evaluated its association with hematologic parameters. Expression of EPAS1 mRNA was detected in all eight tissues （heart, liver, lung, spleen, pancreas, kidney, muscles and ovary）. The expressions of EPAS1 in lung and pancreas were extremely higher than other tissues examined. Three novel single nucleotide polymorphisms （SNPs） （g.83052 C〉T, g.83065 G〉A and g.83067 C〉A） within the EPAS1 were identified and genotyped in Pali （PL）, Gannan （GN） and Tianzhu White （TZW） yak breeds. Significant higher frequencies of the AA and GA genotypes and A allele of the g.83065 G〉A were observed in the PL and GN breeds than that in the TZW breed （P〈0.01）. Association analysis of the PL breed indicated that the g.83065 G〉A polymorphism was significantly associated with hemoglobin （HGB） concentration in yaks （P〈0.05）. Individuals with genotype AA had significantly higher HGB concentration （P〈0.05） than those with genotype GA and GG. All these results will help our further understanding of biological functional of yak EPAS1 gene in responding to hypoxia and also indicate EPAS1 might contribute to the hypoxia adaptation of the yak.展开更多
基金supported by the Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province(202201AS070044)National Key Research&Developmental Program of China(2021YFA0805701)+1 种基金Chinese Academy of Sciences(CAS)“Light of West China”Program(xbzg-zdsys-202113)Kunming Science and Technology Bureau(2022SCP007)。
文摘Telomeres are nucleoprotein structures located at the end of each chromosome,which function in terminal protection and genomic stability.Telomeric damage is closely related to replicative senescence in vitro and physical aging in vivo.As relatively long-lived mammals based on body size,bats display unique telomeric patterns,including the upregulation of genes involved in alternative lengthening of telomeres(ALT),DNA repair,and DNA replication.At present,however,the relevant molecular mechanisms remain unclear.In this study,we performed cross-species comparison and identified EPAS1,a well-defined oxygen response gene,as a key telomeric protector in bat fibroblasts.Bat fibroblasts showed high expression of EPAS1,which enhanced the transcription of shelterin components TRF1 and TRF2,as well as DNA repair factor RAD50,conferring bat fibroblasts with resistance to senescence during long-term consecutive expansion.Based on a human single-cell transcriptome atlas,we found that EPAS1 was predominantly expressed in the human pulmonary endothelial cell subpopulation.Using in vitro-cultured human pulmonary endothelial cells,we confirmed the functional and mechanistic conservation of EPAS1 in telomeric protection between bats and humans.In addition,the EPAS1 agonist M1001 was shown to be a protective compound against bleomycin-induced pulmonary telomeric damage and senescence.In conclusion,we identified a potential mechanism for regulating telomere stability in human pulmonary diseases associated with aging,drawing insights from the longevity of bats.
基金Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of China
文摘AIM: To evaluate the prognostic signif icance of HIF- 2α/EPAS1 expression in hepatocellular carcinoma (HCC). METHODS: Surgical specimens from 315 patients with HCC as well as 196 adjacent noncancerous lesions and 22 cases of normal liver tissue were investigated by immunohistochemistry (IHC) for HIF-2α/EPAS1 using a standard detection system. Correlations with clinicopathological factors, VEGF, microvessel density (MVD), and prognosis were analyzed. RESULTS: Immunoreactivity of HIF-2α/EPAS1 was positive in 69.5% of HCC, 55.6% of adjacent noncancerous tissue, and 0% of normal liver tissue. And it was significantly correlated with tumor grade, venous invasion, intrahepatic metastasis, necrosis, and capsule infiltration. Correlation analysis of HIF-2α/EPAS1 with angiogenic factor VEGF (P < 0.001), and MVD (P = 0.016) was also noted. HIF-2α/EPAS1 protein was less frequently expressed in low MVD cases, whereas a high rate of expression was noted in cases with both medium and high MVD (P = 0.042). By Kaplan-Meier analysis, strong HIF-2α/EPAS1 staining (> 50% of tumor cells) in HCC correlated with a shortened survival in patients (Cox's regression, P < 0.001, r = 3.699). CONCLUSION: We conclude that HIF-2α/EPAS1 expression may play an important role in tumor progression and prognosis of HCC. Assessment of HIF-2α/EPAS1 expression in HCC may be used as a diagnostic tool and possibly a target in the treatment of HCC.
基金supported by the Special Fund for Agro-scientific Research in the Public Interest,China (201003061)the Key Technologies R&D Program of China during the 12thFive-Year Plan period (2012BAD13B05)+1 种基金the Great Project of Science and Technology of Gansu Province in China (1102NKDA027)the National Natural Science Foundation of China (31101702)
文摘Endothelial PAS domain protein 1 gene （EPAS1） is a key transcription factor that activates the expression of oxygen-regu- lated genes. In this study, in order to better understand the effects of EPAS1 gene on hematologic parameters in yak, we firstly quantified the tissue expression patterns for EPASl mRNA of yak, identified polymorphism in this gene and evaluated its association with hematologic parameters. Expression of EPAS1 mRNA was detected in all eight tissues （heart, liver, lung, spleen, pancreas, kidney, muscles and ovary）. The expressions of EPAS1 in lung and pancreas were extremely higher than other tissues examined. Three novel single nucleotide polymorphisms （SNPs） （g.83052 C〉T, g.83065 G〉A and g.83067 C〉A） within the EPAS1 were identified and genotyped in Pali （PL）, Gannan （GN） and Tianzhu White （TZW） yak breeds. Significant higher frequencies of the AA and GA genotypes and A allele of the g.83065 G〉A were observed in the PL and GN breeds than that in the TZW breed （P〈0.01）. Association analysis of the PL breed indicated that the g.83065 G〉A polymorphism was significantly associated with hemoglobin （HGB） concentration in yaks （P〈0.05）. Individuals with genotype AA had significantly higher HGB concentration （P〈0.05） than those with genotype GA and GG. All these results will help our further understanding of biological functional of yak EPAS1 gene in responding to hypoxia and also indicate EPAS1 might contribute to the hypoxia adaptation of the yak.
