Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells
Proper telomere length is essential for indefinite self-renewal of embryonic stem (ES) cells and cancer cells. Telomerase-deficient late generation mouse ES cells and human ALT cancer cells are able to propagate for numerous passages, suggesting telomerase-independent mechanisms responding for telom...
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MDPI AG
2022-01-01
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| author | Jiameng Dan Zhongcheng Zhou Fang Wang Hua Wang Renpeng Guo David L. Keefe Lin Liu |
| author_facet | Jiameng Dan Zhongcheng Zhou Fang Wang Hua Wang Renpeng Guo David L. Keefe Lin Liu |
| author_sort | Jiameng Dan |
| collection | DOAJ |
| description | Proper telomere length is essential for indefinite self-renewal of embryonic stem (ES) cells and cancer cells. Telomerase-deficient late generation mouse ES cells and human ALT cancer cells are able to propagate for numerous passages, suggesting telomerase-independent mechanisms responding for telomere maintenance. However, the underlying mechanisms ensuring the telomere length maintenance are unclear. Here, using late generation telomerase KO (G4 Terc<sup>-/-</sup>) ESCs as a model, we show that <i>Zscan4</i>, highly upregulated in G4 Terc<sup>-/-</sup> ESCs, is responsible for the prolonged culture of these cells with stably short telomeres. Mechanistically, G4 Terc<sup>-/-</sup> ESCs showed reduced levels of DNA methylation and H3K9me3 at Zscan4 promoter and subtelomeres, which relieved the expression of Zscan4. Similarly, human ZSCAN4 was also derepressed by reduced H3K9me3 at its promoter in ALT U2 OS cells, and depletion of ZSCAN4 significantly shortened telomeres. Our results define a similar conserved pathway contributing to the telomere maintenance in telomerase-deficient late generation mESCs and human ALT U2OS cancer cells. |
| first_indexed | 2024-03-10T00:03:30Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T00:03:30Z |
| publishDate | 2022-01-01 |
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| spelling | doaj.art-a8a782cc76594e9ea8fe3fe9fc504c212023-11-23T16:12:11ZengMDPI AGCells2073-44092022-01-0111345610.3390/cells11030456Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer CellsJiameng Dan0Zhongcheng Zhou1Fang Wang2Hua Wang3Renpeng Guo4David L. Keefe5Lin Liu6State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, ChinaState Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, ChinaDepartment of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY 10016, USAState Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, ChinaState Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, ChinaDepartment of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY 10016, USAState Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, ChinaProper telomere length is essential for indefinite self-renewal of embryonic stem (ES) cells and cancer cells. Telomerase-deficient late generation mouse ES cells and human ALT cancer cells are able to propagate for numerous passages, suggesting telomerase-independent mechanisms responding for telomere maintenance. However, the underlying mechanisms ensuring the telomere length maintenance are unclear. Here, using late generation telomerase KO (G4 Terc<sup>-/-</sup>) ESCs as a model, we show that <i>Zscan4</i>, highly upregulated in G4 Terc<sup>-/-</sup> ESCs, is responsible for the prolonged culture of these cells with stably short telomeres. Mechanistically, G4 Terc<sup>-/-</sup> ESCs showed reduced levels of DNA methylation and H3K9me3 at Zscan4 promoter and subtelomeres, which relieved the expression of Zscan4. Similarly, human ZSCAN4 was also derepressed by reduced H3K9me3 at its promoter in ALT U2 OS cells, and depletion of ZSCAN4 significantly shortened telomeres. Our results define a similar conserved pathway contributing to the telomere maintenance in telomerase-deficient late generation mESCs and human ALT U2OS cancer cells.https://www.mdpi.com/2073-4409/11/3/456Zscan4telomereES cellsALTDNA methylationH3K9me3 |
| spellingShingle | Jiameng Dan Zhongcheng Zhou Fang Wang Hua Wang Renpeng Guo David L. Keefe Lin Liu Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells Cells Zscan4 telomere ES cells ALT DNA methylation H3K9me3 |
| title | Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells |
| title_full | Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells |
| title_fullStr | Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells |
| title_full_unstemmed | Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells |
| title_short | Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells |
| title_sort | zscan4 contributes to telomere maintenance in telomerase deficient late generation mouse escs and human alt cancer cells |
| topic | Zscan4 telomere ES cells ALT DNA methylation H3K9me3 |
| url | https://www.mdpi.com/2073-4409/11/3/456 |
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