TET1 Catalytic Activity is Required for Reprogramming of Imprinting Control Regions and Patterning of Sperm-Specific Hypomethylated Regions
DNA methylation erasure is required for mammalian primordial germ cell reprogramming. TET enzymes iteratively oxidize 5-methylcytosine to generate 5-hyroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxycytosine to facilitate active genome demethylation. Whether these bases are required to promote replication-coupled dilution or activate base excision repair during germline reprogramming remains unresolved due to the lack of genetic models that decouple TET activities. Here, we generated two mouse lines expressing catalytically inactive TET1 ( Tet1-HxD ) and TET1 that stalls oxidation at 5hmC ( Tet1-V ). Tet1 -/- , Tet1 V/V , and Tet1 HxD/HxD sperm methylomes show that TET1 V and TET1 HxD rescue most Tet1 -/- hypermethylated regions, demonstrating the importance of TET1’s extra-catalytic functions. Imprinted regions, in contrast, require iterative oxidation. We further reveal a broader class of hypermethylated regions in sperm of Tet1 mutant mice that are excluded from de novo methylation during male germline development and depend on TET oxidation for reprogramming. Our study underscores the link between TET1-mediated demethylation during reprogramming and sperm methylome patterning.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2023) vom: 21. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Prasasya, Rexxi D [VerfasserIn] |
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Date Revised 23.04.2024 published: Electronic UpdateIn: Dev Cell. 2024 Apr 1;:. - PMID 38569549 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.02.21.529426 |
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| PPN (Katalog-ID): |
NLM353711853 |
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| 500 | |a UpdateIn: Dev Cell. 2024 Apr 1;:. - PMID 38569549 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a DNA methylation erasure is required for mammalian primordial germ cell reprogramming. TET enzymes iteratively oxidize 5-methylcytosine to generate 5-hyroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxycytosine to facilitate active genome demethylation. Whether these bases are required to promote replication-coupled dilution or activate base excision repair during germline reprogramming remains unresolved due to the lack of genetic models that decouple TET activities. Here, we generated two mouse lines expressing catalytically inactive TET1 ( Tet1-HxD ) and TET1 that stalls oxidation at 5hmC ( Tet1-V ). Tet1 -/- , Tet1 V/V , and Tet1 HxD/HxD sperm methylomes show that TET1 V and TET1 HxD rescue most Tet1 -/- hypermethylated regions, demonstrating the importance of TET1’s extra-catalytic functions. Imprinted regions, in contrast, require iterative oxidation. We further reveal a broader class of hypermethylated regions in sperm of Tet1 mutant mice that are excluded from de novo methylation during male germline development and depend on TET oxidation for reprogramming. Our study underscores the link between TET1-mediated demethylation during reprogramming and sperm methylome patterning | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Caldwell, Blake A |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhengfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Songze |e verfasserin |4 aut | |
| 700 | 1 | |a Leu, Nicolae A |e verfasserin |4 aut | |
| 700 | 1 | |a Fowler, Johanna M |e verfasserin |4 aut | |
| 700 | 1 | |a Cincotta, Steven A |e verfasserin |4 aut | |
| 700 | 1 | |a Laird, Diana J |e verfasserin |4 aut | |
| 700 | 1 | |a Kohli, Rahul M |e verfasserin |4 aut | |
| 700 | 1 | |a Bartolomei, Marisa S |e verfasserin |4 aut | |
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