Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation
Abstract Background Vitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone demethylases. The epigenetic remodelling promoted by vitC improves the efficiency of induced pluripotent stem cell...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Epigenetics & Chromatin |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13072-023-00514-6 |
| _version_ | 1797556411398356992 |
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| author | Kevin C. L. Cheng Jennifer M. Frost Francisco J. Sánchez-Luque Marta García-Canãdas Darren Taylor Wan R. Yang Branavy Irayanar Swetha Sampath Hemalvi Patani Karl Agger Kristian Helin Gabriella Ficz Kathleen H. Burns Adam Ewing José L. García-Pérez Miguel R. Branco |
| author_facet | Kevin C. L. Cheng Jennifer M. Frost Francisco J. Sánchez-Luque Marta García-Canãdas Darren Taylor Wan R. Yang Branavy Irayanar Swetha Sampath Hemalvi Patani Karl Agger Kristian Helin Gabriella Ficz Kathleen H. Burns Adam Ewing José L. García-Pérez Miguel R. Branco |
| author_sort | Kevin C. L. Cheng |
| collection | DOAJ |
| description | Abstract Background Vitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone demethylases. The epigenetic remodelling promoted by vitC improves the efficiency of induced pluripotent stem cell derivation, and is required to attain a ground-state of pluripotency in embryonic stem cells (ESCs) that closely mimics the inner cell mass of the early blastocyst. However, genome-wide DNA and histone demethylation can lead to upregulation of transposable elements (TEs), and it is not known how vitC addition in culture media affects TE expression in pluripotent stem cells. Results Here we show that vitC increases the expression of several TE families, including evolutionarily young LINE-1 (L1) elements, in mouse ESCs. We find that TET activity is dispensable for L1 upregulation, and that instead it occurs largely as a result of H3K9me3 loss mediated by KDM4A/C histone demethylases. Despite increased L1 levels, we did not detect increased somatic insertion rates in vitC-treated cells. Notably, treatment of human ESCs with vitC also increases L1 protein levels, albeit through a distinct, post-transcriptional mechanism. Conclusion VitC directly modulates the expression of mouse L1s and other TEs through epigenetic mechanisms, with potential for downstream effects related to the multiple emerging roles of L1s in cellular function. |
| first_indexed | 2024-03-10T17:01:28Z |
| format | Article |
| id | doaj.art-f795feb9ee214159af694527040dae95 |
| institution | Directory Open Access Journal |
| issn | 1756-8935 |
| language | English |
| last_indexed | 2024-03-10T17:01:28Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Epigenetics & Chromatin |
| spelling | doaj.art-f795feb9ee214159af694527040dae952023-11-20T10:57:29ZengBMCEpigenetics & Chromatin1756-89352023-10-0116111610.1186/s13072-023-00514-6Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylationKevin C. L. Cheng0Jennifer M. Frost1Francisco J. Sánchez-Luque2Marta García-Canãdas3Darren Taylor4Wan R. Yang5Branavy Irayanar6Swetha Sampath7Hemalvi Patani8Karl Agger9Kristian Helin10Gabriella Ficz11Kathleen H. Burns12Adam Ewing13José L. García-Pérez14Miguel R. Branco15Blizard Institute, Faculty of Medicine and Dentistry, QMULBlizard Institute, Faculty of Medicine and Dentistry, QMULInstitute of Parasitology and Biomedicine “Lopez-Neyra” (IPBLN), Spanish National Research Council (CSIC), PTS GranadaPfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research (GENYO), PTS GranadaBlizard Institute, Faculty of Medicine and Dentistry, QMULDepartment of Pathology, Johns Hopkins University School of MedicineBlizard Institute, Faculty of Medicine and Dentistry, QMULBlizard Institute, Faculty of Medicine and Dentistry, QMULBarts Cancer Institute, Faculty of Medicine and Dentistry, QMULThe Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of CopenhagenThe Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of CopenhagenBarts Cancer Institute, Faculty of Medicine and Dentistry, QMULDepartment of Oncologic Pathology, Dana-Farber Cancer InstituteMater Research Institute, University of QueenslandPfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research (GENYO), PTS GranadaBlizard Institute, Faculty of Medicine and Dentistry, QMULAbstract Background Vitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone demethylases. The epigenetic remodelling promoted by vitC improves the efficiency of induced pluripotent stem cell derivation, and is required to attain a ground-state of pluripotency in embryonic stem cells (ESCs) that closely mimics the inner cell mass of the early blastocyst. However, genome-wide DNA and histone demethylation can lead to upregulation of transposable elements (TEs), and it is not known how vitC addition in culture media affects TE expression in pluripotent stem cells. Results Here we show that vitC increases the expression of several TE families, including evolutionarily young LINE-1 (L1) elements, in mouse ESCs. We find that TET activity is dispensable for L1 upregulation, and that instead it occurs largely as a result of H3K9me3 loss mediated by KDM4A/C histone demethylases. Despite increased L1 levels, we did not detect increased somatic insertion rates in vitC-treated cells. Notably, treatment of human ESCs with vitC also increases L1 protein levels, albeit through a distinct, post-transcriptional mechanism. Conclusion VitC directly modulates the expression of mouse L1s and other TEs through epigenetic mechanisms, with potential for downstream effects related to the multiple emerging roles of L1s in cellular function.https://doi.org/10.1186/s13072-023-00514-6Vitamin CLINE-1Embryonic stem cellsMouseHuman2-oxoglutarate-dependent dioxygenases |
| spellingShingle | Kevin C. L. Cheng Jennifer M. Frost Francisco J. Sánchez-Luque Marta García-Canãdas Darren Taylor Wan R. Yang Branavy Irayanar Swetha Sampath Hemalvi Patani Karl Agger Kristian Helin Gabriella Ficz Kathleen H. Burns Adam Ewing José L. García-Pérez Miguel R. Branco Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation Epigenetics & Chromatin Vitamin C LINE-1 Embryonic stem cells Mouse Human 2-oxoglutarate-dependent dioxygenases |
| title | Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation |
| title_full | Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation |
| title_fullStr | Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation |
| title_full_unstemmed | Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation |
| title_short | Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation |
| title_sort | vitamin c activates young line 1 elements in mouse embryonic stem cells via h3k9me3 demethylation |
| topic | Vitamin C LINE-1 Embryonic stem cells Mouse Human 2-oxoglutarate-dependent dioxygenases |
| url | https://doi.org/10.1186/s13072-023-00514-6 |
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