The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases
Multiple epigenetic pathways underlie the temporal order of DNA replication (replication timing) in the contexts of development and disease. DNA methylation by DNA methyltransferases (Dnmts) and downstream chromatin reorganization and transcriptional changes are thought to impact DNA replication, ye...
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MDPI AG
2021-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/2/266 |
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| author | Shin-ichiro Takebayashi Tyrone Ryba Kelsey Wimbish Takuya Hayakawa Morito Sakaue Kenji Kuriya Saori Takahashi Shin Ogata Ichiro Hiratani Katsuzumi Okumura Masaki Okano Masato Ogata |
| author_facet | Shin-ichiro Takebayashi Tyrone Ryba Kelsey Wimbish Takuya Hayakawa Morito Sakaue Kenji Kuriya Saori Takahashi Shin Ogata Ichiro Hiratani Katsuzumi Okumura Masaki Okano Masato Ogata |
| author_sort | Shin-ichiro Takebayashi |
| collection | DOAJ |
| description | Multiple epigenetic pathways underlie the temporal order of DNA replication (replication timing) in the contexts of development and disease. DNA methylation by DNA methyltransferases (Dnmts) and downstream chromatin reorganization and transcriptional changes are thought to impact DNA replication, yet this remains to be comprehensively tested. Using cell-based and genome-wide approaches to measure replication timing, we identified a number of genomic regions undergoing subtle but reproducible replication timing changes in various <i>Dnmt</i>-mutant mouse embryonic stem (ES) cell lines that included a cell line with a drug-inducible Dnmt3a2 expression system. Replication timing within pericentromeric heterochromatin (PH) was shown to be correlated with redistribution of H3K27me3 induced by DNA hypomethylation: Later replicating PH coincided with H3K27me3-enriched regions. In contrast, this relationship with H3K27me3 was not evident within chromosomal arm regions undergoing either early-to-late (EtoL) or late-to-early (LtoE) switching of replication timing upon loss of the Dnmts. Interestingly, Dnmt-sensitive transcriptional up- and downregulation frequently coincided with earlier and later shifts in replication timing of the chromosomal arm regions, respectively. Our study revealed the previously unrecognized complex and diverse effects of the Dnmts loss on the mammalian DNA replication landscape. |
| first_indexed | 2024-03-09T03:18:42Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T03:18:42Z |
| publishDate | 2021-01-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-34deeb6edbe3441688a6f882879d3d022023-12-03T15:12:24ZengMDPI AGCells2073-44092021-01-0110226610.3390/cells10020266The Temporal Order of DNA Replication Shaped by Mammalian DNA MethyltransferasesShin-ichiro Takebayashi0Tyrone Ryba1Kelsey Wimbish2Takuya Hayakawa3Morito Sakaue4Kenji Kuriya5Saori Takahashi6Shin Ogata7Ichiro Hiratani8Katsuzumi Okumura9Masaki Okano10Masato Ogata11Laboratory of Molecular and Cellular Biology, Graduate School of Bioresources, Mie University, Tsu, Mie 514-8507, JapanDivision of Natural Sciences, New College of Florida, Sarasota, FL 34243, USADivision of Natural Sciences, New College of Florida, Sarasota, FL 34243, USALaboratory of Molecular and Cellular Biology, Graduate School of Bioresources, Mie University, Tsu, Mie 514-8507, JapanDepartment of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, JapanLaboratory of Molecular and Cellular Biology, Graduate School of Bioresources, Mie University, Tsu, Mie 514-8507, JapanLaboratory for Developmental Epigenetics, RIKEN BDR, Kobe, Hyogo 650-0047, JapanLaboratory of Molecular and Cellular Biology, Graduate School of Bioresources, Mie University, Tsu, Mie 514-8507, JapanLaboratory for Developmental Epigenetics, RIKEN BDR, Kobe, Hyogo 650-0047, JapanLaboratory of Molecular and Cellular Biology, Graduate School of Bioresources, Mie University, Tsu, Mie 514-8507, JapanInstitute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, JapanDepartment of Biochemistry and Proteomics, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, JapanMultiple epigenetic pathways underlie the temporal order of DNA replication (replication timing) in the contexts of development and disease. DNA methylation by DNA methyltransferases (Dnmts) and downstream chromatin reorganization and transcriptional changes are thought to impact DNA replication, yet this remains to be comprehensively tested. Using cell-based and genome-wide approaches to measure replication timing, we identified a number of genomic regions undergoing subtle but reproducible replication timing changes in various <i>Dnmt</i>-mutant mouse embryonic stem (ES) cell lines that included a cell line with a drug-inducible Dnmt3a2 expression system. Replication timing within pericentromeric heterochromatin (PH) was shown to be correlated with redistribution of H3K27me3 induced by DNA hypomethylation: Later replicating PH coincided with H3K27me3-enriched regions. In contrast, this relationship with H3K27me3 was not evident within chromosomal arm regions undergoing either early-to-late (EtoL) or late-to-early (LtoE) switching of replication timing upon loss of the Dnmts. Interestingly, Dnmt-sensitive transcriptional up- and downregulation frequently coincided with earlier and later shifts in replication timing of the chromosomal arm regions, respectively. Our study revealed the previously unrecognized complex and diverse effects of the Dnmts loss on the mammalian DNA replication landscape.https://www.mdpi.com/2073-4409/10/2/266DNA replicationreplication timingDNA methyltransferases |
| spellingShingle | Shin-ichiro Takebayashi Tyrone Ryba Kelsey Wimbish Takuya Hayakawa Morito Sakaue Kenji Kuriya Saori Takahashi Shin Ogata Ichiro Hiratani Katsuzumi Okumura Masaki Okano Masato Ogata The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases Cells DNA replication replication timing DNA methyltransferases |
| title | The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases |
| title_full | The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases |
| title_fullStr | The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases |
| title_full_unstemmed | The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases |
| title_short | The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases |
| title_sort | temporal order of dna replication shaped by mammalian dna methyltransferases |
| topic | DNA replication replication timing DNA methyltransferases |
| url | https://www.mdpi.com/2073-4409/10/2/266 |
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