EPAS1 prevents telomeric damage-induced senescence by enhancing transcription of TRF1,TRF2,and RAD50  

作　　者：Kai-Qin Li Gao-Jing Liu Xiu-Yun Liu Qiong-Fang Chen Xiao-Yan Huang Qiu Tu Jiao Zhang Qing Chang Yun-Hua Xie Rong Hua Dong-Ming Xu Zhen Liu Bo Zhao 

机构地区：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences&Yunnan Province,KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming,Yunnan 650201,China [2]State Key Laboratory of Genetic Resources and Evolution,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming,Yunnan 650201,China [3]University of Chinese Academy of Sciences,Beijing 100049,China [4]Primate Facility,National Research Facility for Phenotypic&Genetic Analysis of Model Animals,and National Resource Center for Non-Human Primates,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming,Yunnan 650201,China

出　　处：《Zoological Research》2023年第3期636-649,共14页动物学研究（英文）

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);Chinese Academy of Sciences(CAS)“Light of West China”Program(xbzg-zdsys-202113);Kunming Science and Technology Bureau(2022SCP007)。

摘　　要：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.

关 键 词：Bat TELOMERE SENESCENCE EPAS1 M1001 Pulmonary endothelial cell 

分 类 号：Q75[生物学—分子生物学]