SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells
Abstract Background Endogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation a...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-01-01
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| Series: | Genome Biology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13059-017-1376-y |
| _version_ | 1819069014710681600 |
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| author | Özgen Deniz Lorenzo de la Rica Kevin C. L. Cheng Dominik Spensberger Miguel R. Branco |
| author_facet | Özgen Deniz Lorenzo de la Rica Kevin C. L. Cheng Dominik Spensberger Miguel R. Branco |
| author_sort | Özgen Deniz |
| collection | DOAJ |
| description | Abstract Background Endogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET-dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos. Results We use naïve ESCs to investigate the role of SETDB1 in ERV regulation and its relationship with TET-mediated DNA demethylation. Naïve ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We find that in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these retrotransposons indirectly. Instead, SETDB1 depletion leads to a TET2-dependent loss of H4R3me2s, which is indispensable for IAP silencing during epigenetic reprogramming. Conclusions Our results demonstrate a novel and unexpected role for SETDB1 in protecting IAPs from TET2-dependent histone arginine demethylation. |
| first_indexed | 2024-12-21T16:43:19Z |
| format | Article |
| id | doaj.art-5db2c048c1904a08b795ee8bc5edc186 |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-21T16:43:19Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-5db2c048c1904a08b795ee8bc5edc1862022-12-21T18:57:03ZengBMCGenome Biology1474-760X2018-01-0119111110.1186/s13059-017-1376-ySETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cellsÖzgen Deniz0Lorenzo de la Rica1Kevin C. L. Cheng2Dominik Spensberger3Miguel R. Branco4Blizard Institute, Barts and The London School of Medicine and Dentistry, QMULBlizard Institute, Barts and The London School of Medicine and Dentistry, QMULBlizard Institute, Barts and The London School of Medicine and Dentistry, QMULDepartment of Haematology, Cambridge Institute for Medical Research, University of CambridgeBlizard Institute, Barts and The London School of Medicine and Dentistry, QMULAbstract Background Endogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET-dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos. Results We use naïve ESCs to investigate the role of SETDB1 in ERV regulation and its relationship with TET-mediated DNA demethylation. Naïve ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We find that in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these retrotransposons indirectly. Instead, SETDB1 depletion leads to a TET2-dependent loss of H4R3me2s, which is indispensable for IAP silencing during epigenetic reprogramming. Conclusions Our results demonstrate a novel and unexpected role for SETDB1 in protecting IAPs from TET2-dependent histone arginine demethylation.http://link.springer.com/article/10.1186/s13059-017-1376-yEmbryonic stem cellsRetrotransposonsIntracisternal A particles (IAPs)SETDB1Ten-eleven translocation enzymesDNA methylation |
| spellingShingle | Özgen Deniz Lorenzo de la Rica Kevin C. L. Cheng Dominik Spensberger Miguel R. Branco SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells Genome Biology Embryonic stem cells Retrotransposons Intracisternal A particles (IAPs) SETDB1 Ten-eleven translocation enzymes DNA methylation |
| title | SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells |
| title_full | SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells |
| title_fullStr | SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells |
| title_full_unstemmed | SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells |
| title_short | SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells |
| title_sort | setdb1 prevents tet2 dependent activation of iap retroelements in naive embryonic stem cells |
| topic | Embryonic stem cells Retrotransposons Intracisternal A particles (IAPs) SETDB1 Ten-eleven translocation enzymes DNA methylation |
| url | http://link.springer.com/article/10.1186/s13059-017-1376-y |
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