Tissue-specific roles of de novo DNA methyltransferases
Abstract DNA methylation, catalyzed by DNA methyltransferases (DNMT), plays pivotal role in regulating embryonic development, gene expression, adaption to environmental stress, and maintaining genome integrity. DNMT family consists of DNMT1, DNMT3A, DNMT3B, and the enzymatically inactive DNMT3L. DNM...
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BMC
2025-01-01
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| Series: | Epigenetics & Chromatin |
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| Online Access: | https://doi.org/10.1186/s13072-024-00566-2 |
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| author | Dániel Márton Tóth Flóra Szeri Mária Ashaber Muhyiddeen Muazu Lóránt Székvölgyi Tamás Arányi |
| author_facet | Dániel Márton Tóth Flóra Szeri Mária Ashaber Muhyiddeen Muazu Lóránt Székvölgyi Tamás Arányi |
| author_sort | Dániel Márton Tóth |
| collection | DOAJ |
| description | Abstract DNA methylation, catalyzed by DNA methyltransferases (DNMT), plays pivotal role in regulating embryonic development, gene expression, adaption to environmental stress, and maintaining genome integrity. DNMT family consists of DNMT1, DNMT3A, DNMT3B, and the enzymatically inactive DNMT3L. DNMT3A and DNMT3B establish novel methylation patterns maintained by DNMT1 during replication. Genetic variants of DNMT3A and DNMT3B cause rare diseases such as Tatton-Brown-Rahman and ICF syndromes. Additionally, somatic mutations cause common conditions such as osteoarthritis, osteoporosis, clonal hematopoiesis of indeterminate potential (CHIP), hematologic malignancies, and cancer. While DNMTs have been extensively studied in vitro, in early development and in disease, their detailed physiologic roles remain less understood as in vivo investigations are hindered by the embryonic or perinatal lethality of the knockout mice. To circumvent this problem, tissue-specific Dnmt3a and Dnmt3b knockouts were engineered. This review explores their diverse molecular roles across various organs and cell types and characterizes the phenotype of the knockout mice. We provide a comprehensive collection of over forty tissue-specific knockout models generated by cre recombinase. We highlight the distinct functions of DNMT3A and DNMT3B in germ cells, early development, uterus, hematopoietic differentiation, musculoskeletal development, visceral organs, and nervous system. Our findings indicate that DNMT3A primarily regulates hematopoietic differentiation, while DNMT3B is crucial for cartilage homeostasis and ossification. We emphasize the context-dependent roles of DNMT3A and DNMT3B and demonstrate that they also complement DNMT1 maintenance methyltransferase activity. Overall, the expression patterns of DNMTs across tissues provide insights into potential therapeutic applications for treating neurologic diseases, cancer, and osteoporosis. |
| format | Article |
| id | doaj-art-2e08d3ae13eb48f8a3ab41b44161f42e |
| institution | Kabale University |
| issn | 1756-8935 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Epigenetics & Chromatin |
| spelling | doaj-art-2e08d3ae13eb48f8a3ab41b44161f42e2025-01-19T12:39:06ZengBMCEpigenetics & Chromatin1756-89352025-01-0118111610.1186/s13072-024-00566-2Tissue-specific roles of de novo DNA methyltransferasesDániel Márton Tóth0Flóra Szeri1Mária Ashaber2Muhyiddeen Muazu3Lóránt Székvölgyi4Tamás Arányi5Department of Molecular Biology, Semmelweis UniversityInstitute of Molecular Life Sciences, HUN-REN Research Centre for Natural SciencesDepartment of Molecular Biology, Semmelweis UniversityDepartment of Molecular Biology, Semmelweis UniversityDepartment of Molecular and Nanopharmaceutics, Genome Architecture and Recombination Research Group, Faculty of Pharmacy, MTA-DE Momentum, University of DebrecenDepartment of Molecular Biology, Semmelweis UniversityAbstract DNA methylation, catalyzed by DNA methyltransferases (DNMT), plays pivotal role in regulating embryonic development, gene expression, adaption to environmental stress, and maintaining genome integrity. DNMT family consists of DNMT1, DNMT3A, DNMT3B, and the enzymatically inactive DNMT3L. DNMT3A and DNMT3B establish novel methylation patterns maintained by DNMT1 during replication. Genetic variants of DNMT3A and DNMT3B cause rare diseases such as Tatton-Brown-Rahman and ICF syndromes. Additionally, somatic mutations cause common conditions such as osteoarthritis, osteoporosis, clonal hematopoiesis of indeterminate potential (CHIP), hematologic malignancies, and cancer. While DNMTs have been extensively studied in vitro, in early development and in disease, their detailed physiologic roles remain less understood as in vivo investigations are hindered by the embryonic or perinatal lethality of the knockout mice. To circumvent this problem, tissue-specific Dnmt3a and Dnmt3b knockouts were engineered. This review explores their diverse molecular roles across various organs and cell types and characterizes the phenotype of the knockout mice. We provide a comprehensive collection of over forty tissue-specific knockout models generated by cre recombinase. We highlight the distinct functions of DNMT3A and DNMT3B in germ cells, early development, uterus, hematopoietic differentiation, musculoskeletal development, visceral organs, and nervous system. Our findings indicate that DNMT3A primarily regulates hematopoietic differentiation, while DNMT3B is crucial for cartilage homeostasis and ossification. We emphasize the context-dependent roles of DNMT3A and DNMT3B and demonstrate that they also complement DNMT1 maintenance methyltransferase activity. Overall, the expression patterns of DNMTs across tissues provide insights into potential therapeutic applications for treating neurologic diseases, cancer, and osteoporosis.https://doi.org/10.1186/s13072-024-00566-2DNA methylationDe novo methyltransferaseDnmt3aDnmt3bKnockoutCre recombinase |
| spellingShingle | Dániel Márton Tóth Flóra Szeri Mária Ashaber Muhyiddeen Muazu Lóránt Székvölgyi Tamás Arányi Tissue-specific roles of de novo DNA methyltransferases Epigenetics & Chromatin DNA methylation De novo methyltransferase Dnmt3a Dnmt3b Knockout Cre recombinase |
| title | Tissue-specific roles of de novo DNA methyltransferases |
| title_full | Tissue-specific roles of de novo DNA methyltransferases |
| title_fullStr | Tissue-specific roles of de novo DNA methyltransferases |
| title_full_unstemmed | Tissue-specific roles of de novo DNA methyltransferases |
| title_short | Tissue-specific roles of de novo DNA methyltransferases |
| title_sort | tissue specific roles of de novo dna methyltransferases |
| topic | DNA methylation De novo methyltransferase Dnmt3a Dnmt3b Knockout Cre recombinase |
| url | https://doi.org/10.1186/s13072-024-00566-2 |
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