Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity
Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using...
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.726345/full |
| _version_ | 1819242941607051264 |
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| author | Di-Xian Wang Xu-Dong Zhu Xiao-Ru Ma Li-Bin Wang Zhao-Jun Dong Rong-Rong Lin Yi-Na Cao Jing-Wei Zhao |
| author_facet | Di-Xian Wang Xu-Dong Zhu Xiao-Ru Ma Li-Bin Wang Zhao-Jun Dong Rong-Rong Lin Yi-Na Cao Jing-Wei Zhao |
| author_sort | Di-Xian Wang |
| collection | DOAJ |
| description | Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs. |
| first_indexed | 2024-12-23T14:47:48Z |
| format | Article |
| id | doaj.art-acd28cf4a417414f8e5fc184cab96e45 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-23T14:47:48Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-acd28cf4a417414f8e5fc184cab96e452022-12-21T17:43:03ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-09-011210.3389/fphys.2021.726345726345Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase ActivityDi-Xian Wang0Xu-Dong Zhu1Xiao-Ru Ma2Li-Bin Wang3Zhao-Jun Dong4Rong-Rong Lin5Yi-Na Cao6Jing-Wei Zhao7Department of Pathology and Department of Human Anatomy, Histology, and Embryology, Sir Run Run Shaw Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, ChinaInstitute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, ChinaDepartment of Pathology and Department of Human Anatomy, Histology, and Embryology, Sir Run Run Shaw Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, ChinaThe General Hospital of Ningxia Medical University, Yinchuan, ChinaDepartment of Pathology and Department of Human Anatomy, Histology, and Embryology, Sir Run Run Shaw Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pathology and Department of Human Anatomy, Histology, and Embryology, Sir Run Run Shaw Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pathology and Department of Human Anatomy, Histology, and Embryology, Sir Run Run Shaw Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pathology and Department of Human Anatomy, Histology, and Embryology, Sir Run Run Shaw Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, ChinaMaintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.https://www.frontiersin.org/articles/10.3389/fphys.2021.726345/fullgrowth differentiation factor 11telomere lengthTERTTERCtelomerase activitySmad2 |
| spellingShingle | Di-Xian Wang Xu-Dong Zhu Xiao-Ru Ma Li-Bin Wang Zhao-Jun Dong Rong-Rong Lin Yi-Na Cao Jing-Wei Zhao Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity Frontiers in Physiology growth differentiation factor 11 telomere length TERT TERC telomerase activity Smad2 |
| title | Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity |
| title_full | Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity |
| title_fullStr | Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity |
| title_full_unstemmed | Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity |
| title_short | Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity |
| title_sort | loss of growth differentiation factor 11 shortens telomere length by downregulating telomerase activity |
| topic | growth differentiation factor 11 telomere length TERT TERC telomerase activity Smad2 |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.726345/full |
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