TET1 displays catalytic and non-catalytic functions in the adult mouse cortex
TET1/2/3 dioxygenases iteratively demethylate 5-methylcytosine, beginning with the formation of 5-hydroxymethylcytosine (5hmC). The post-mitotic brain maintains higher levels of 5hmC than most peripheral tissues, and TET1 ablation studies have underscored the critical role of TET1 in brain physiolog...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Epigenetics |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15592294.2024.2374979 |
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| author | Yee Hoon Foong Blake Caldwell Joanne L. Thorvaldsen Christopher Krapp Clementina A. Mesaros Wanding Zhou Rahul M. Kohli Marisa S. Bartolomei |
| author_facet | Yee Hoon Foong Blake Caldwell Joanne L. Thorvaldsen Christopher Krapp Clementina A. Mesaros Wanding Zhou Rahul M. Kohli Marisa S. Bartolomei |
| author_sort | Yee Hoon Foong |
| collection | DOAJ |
| description | TET1/2/3 dioxygenases iteratively demethylate 5-methylcytosine, beginning with the formation of 5-hydroxymethylcytosine (5hmC). The post-mitotic brain maintains higher levels of 5hmC than most peripheral tissues, and TET1 ablation studies have underscored the critical role of TET1 in brain physiology. However, deletion of Tet1 precludes the disentangling of the catalytic and non-catalytic functions of TET1. Here, we dissect these functions of TET1 by comparing adult cortex of Tet1 wildtype (Tet1 WT), a novel Tet1 catalytically dead mutant (Tet1 HxD), and Tet1 knockout (Tet1 KO) mice. Using DNA methylation array, we uncover that Tet1 HxD and KO mutations perturb the methylation status of distinct subsets of CpG sites. Gene ontology (GO) analysis on specific differential 5hmC regions indicates that TET1’s catalytic activity is linked to neuronal-specific functions. RNA-Seq further shows that Tet1 mutations predominantly impact the genes that are associated with alternative splicing. Lastly, we performed High-performance Liquid Chromatography Mass-Spectrometry lipidomics on WT and mutant cortices and uncover accumulation of lysophospholipids lysophosphatidylethanolamine and lysophosphatidylcholine in Tet1 HxD cortex. In summary, we show that Tet1 HxD does not completely phenocopy Tet1 KO, providing evidence that TET1 modulates distinct cortical functions through its catalytic and non-catalytic roles. |
| format | Article |
| id | doaj-art-15da1f095f5e460fb87e5885ecd73cc9 |
| institution | OA Journals |
| issn | 1559-2294 1559-2308 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj-art-15da1f095f5e460fb87e5885ecd73cc92025-08-20T02:20:49ZengTaylor & Francis GroupEpigenetics1559-22941559-23082024-12-0119110.1080/15592294.2024.2374979TET1 displays catalytic and non-catalytic functions in the adult mouse cortexYee Hoon Foong0Blake Caldwell1Joanne L. Thorvaldsen2Christopher Krapp3Clementina A. Mesaros4Wanding Zhou5Rahul M. Kohli6Marisa S. Bartolomei7Department of Cell and Developmental Biology, Perelman School of Medicine, Smilow Center for Translational Research, Philadelphia, PA, USADepartment of Cell and Developmental Biology, Perelman School of Medicine, Smilow Center for Translational Research, Philadelphia, PA, USADepartment of Cell and Developmental Biology, Perelman School of Medicine, Smilow Center for Translational Research, Philadelphia, PA, USADepartment of Cell and Developmental Biology, Perelman School of Medicine, Smilow Center for Translational Research, Philadelphia, PA, USATranslational Biomarkers Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Cell and Developmental Biology, Perelman School of Medicine, Smilow Center for Translational Research, Philadelphia, PA, USATET1/2/3 dioxygenases iteratively demethylate 5-methylcytosine, beginning with the formation of 5-hydroxymethylcytosine (5hmC). The post-mitotic brain maintains higher levels of 5hmC than most peripheral tissues, and TET1 ablation studies have underscored the critical role of TET1 in brain physiology. However, deletion of Tet1 precludes the disentangling of the catalytic and non-catalytic functions of TET1. Here, we dissect these functions of TET1 by comparing adult cortex of Tet1 wildtype (Tet1 WT), a novel Tet1 catalytically dead mutant (Tet1 HxD), and Tet1 knockout (Tet1 KO) mice. Using DNA methylation array, we uncover that Tet1 HxD and KO mutations perturb the methylation status of distinct subsets of CpG sites. Gene ontology (GO) analysis on specific differential 5hmC regions indicates that TET1’s catalytic activity is linked to neuronal-specific functions. RNA-Seq further shows that Tet1 mutations predominantly impact the genes that are associated with alternative splicing. Lastly, we performed High-performance Liquid Chromatography Mass-Spectrometry lipidomics on WT and mutant cortices and uncover accumulation of lysophospholipids lysophosphatidylethanolamine and lysophosphatidylcholine in Tet1 HxD cortex. In summary, we show that Tet1 HxD does not completely phenocopy Tet1 KO, providing evidence that TET1 modulates distinct cortical functions through its catalytic and non-catalytic roles.https://www.tandfonline.com/doi/10.1080/15592294.2024.2374979TET1DNA demethylationDNA hydroxymethylcytosinedioxygenasesadult mouse cortexInfinium BeadChip array |
| spellingShingle | Yee Hoon Foong Blake Caldwell Joanne L. Thorvaldsen Christopher Krapp Clementina A. Mesaros Wanding Zhou Rahul M. Kohli Marisa S. Bartolomei TET1 displays catalytic and non-catalytic functions in the adult mouse cortex Epigenetics TET1 DNA demethylation DNA hydroxymethylcytosine dioxygenases adult mouse cortex Infinium BeadChip array |
| title | TET1 displays catalytic and non-catalytic functions in the adult mouse cortex |
| title_full | TET1 displays catalytic and non-catalytic functions in the adult mouse cortex |
| title_fullStr | TET1 displays catalytic and non-catalytic functions in the adult mouse cortex |
| title_full_unstemmed | TET1 displays catalytic and non-catalytic functions in the adult mouse cortex |
| title_short | TET1 displays catalytic and non-catalytic functions in the adult mouse cortex |
| title_sort | tet1 displays catalytic and non catalytic functions in the adult mouse cortex |
| topic | TET1 DNA demethylation DNA hydroxymethylcytosine dioxygenases adult mouse cortex Infinium BeadChip array |
| url | https://www.tandfonline.com/doi/10.1080/15592294.2024.2374979 |
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