A ternary-code DNA methylome atlas of mouse tissues
Abstract Background DNA cytosine modifications, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), are key epigenetic regulators with distinct functions. Dissecting the ternary code (C, 5mC, 5hmC) across tissues and cell types remains a critical priority due to the limitations of t...
| 出版年: | Genome Biology |
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| 主要な著者: | , , , , , , , , , , , , |
| フォーマット: | 論文 |
| 言語: | 英語 |
| 出版事項: |
BMC
2025-10-01
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| 主題: | |
| オンライン･アクセス: | https://doi.org/10.1186/s13059-025-03808-y |
| _version_ | 1848760069103026176 |
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| author | Sol Moe Lee David C. Goldberg Cameron Cloud Jared B. Parker Christopher Krapp Christian E. Loo Elliot Kim Ivan Zhao Chengcheng Jin Rishi Porecha Marisa S. Bartolomei Rahul M. Kohli Wanding Zhou |
| author_facet | Sol Moe Lee David C. Goldberg Cameron Cloud Jared B. Parker Christopher Krapp Christian E. Loo Elliot Kim Ivan Zhao Chengcheng Jin Rishi Porecha Marisa S. Bartolomei Rahul M. Kohli Wanding Zhou |
| author_sort | Sol Moe Lee |
| collection | DOAJ |
| container_title | Genome Biology |
| description | Abstract Background DNA cytosine modifications, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), are key epigenetic regulators with distinct functions. Dissecting the ternary code (C, 5mC, 5hmC) across tissues and cell types remains a critical priority due to the limitations of traditional profiling methods based on bisulfite conversion. Results Here, we leverage the combined bisulfite and enzymatic (bACE) conversion with the Mouse Methylation BeadChip to generate 265 base-resolution ternary-code modification maps of 5mC and 5hmC across 29 mouse tissue types spanning 8–76 weeks of age and both sexes. Our atlas reveals a complex grammar of 5hmC distribution, jointly shaped by cell mitotic activity, chromatin states, and interplay with 5mC at the same and neighboring CpG sites. Of note, we demonstrate that 5hmC significantly complements 5mC-based biomarkers in delineating cell identity in both brain and non-brain tissues. Each modification state, including 5hmC alone, accurately discriminates tissue types, enabling high-precision machine learning classification of epigenetic identity. Furthermore, the ternary methylome variations extensively implicate gene transcriptional variation, with age-related changes correlated with gene expression in a tissue-dependent manner. Conclusions Our work reveals how tissue, sex, and age jointly govern the dynamics of the two cytosine modifications, augments the scope of DNA modification biomarker discovery, and provides a reference atlas to explore epigenetic dynamics in development and disease. |
| format | Article |
| id | doaj-art-0bc5f36724fa4d1d9e4b3a9477dfb430 |
| institution | Directory of Open Access Journals |
| issn | 1474-760X |
| language | English |
| publishDate | 2025-10-01 |
| publisher | BMC |
| record_format | Article |
| spelling | doaj-art-0bc5f36724fa4d1d9e4b3a9477dfb4302025-10-12T11:33:42ZengBMCGenome Biology1474-760X2025-10-0126113010.1186/s13059-025-03808-yA ternary-code DNA methylome atlas of mouse tissuesSol Moe Lee0David C. Goldberg1Cameron Cloud2Jared B. Parker3Christopher Krapp4Christian E. Loo5Elliot Kim6Ivan Zhao7Chengcheng Jin8Rishi Porecha9Marisa S. Bartolomei10Rahul M. Kohli11Wanding Zhou12Center for Computational and Genomic Medicine, The Children’s Hospital of PhiladelphiaCenter for Computational and Genomic Medicine, The Children’s Hospital of PhiladelphiaCenter for Computational and Genomic Medicine, The Children’s Hospital of PhiladelphiaDepartment of Medicine, University of PennsylvaniaDepartment of Cell and Developmental Biology, Epigenetics Institute, University of Pennsylvania Perelman School of MedicineGraduate Group in Biochemistry and Biophysics, University of PennsylvaniaCenter for Computational and Genomic Medicine, The Children’s Hospital of PhiladelphiaCenter for Computational and Genomic Medicine, The Children’s Hospital of PhiladelphiaDepartment of Cancer Biology, University of Pennsylvania Perelman School of MedicineIllumina, Inc.Department of Cell and Developmental Biology, Epigenetics Institute, University of Pennsylvania Perelman School of MedicineDepartment of Medicine, University of PennsylvaniaCenter for Computational and Genomic Medicine, The Children’s Hospital of PhiladelphiaAbstract Background DNA cytosine modifications, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), are key epigenetic regulators with distinct functions. Dissecting the ternary code (C, 5mC, 5hmC) across tissues and cell types remains a critical priority due to the limitations of traditional profiling methods based on bisulfite conversion. Results Here, we leverage the combined bisulfite and enzymatic (bACE) conversion with the Mouse Methylation BeadChip to generate 265 base-resolution ternary-code modification maps of 5mC and 5hmC across 29 mouse tissue types spanning 8–76 weeks of age and both sexes. Our atlas reveals a complex grammar of 5hmC distribution, jointly shaped by cell mitotic activity, chromatin states, and interplay with 5mC at the same and neighboring CpG sites. Of note, we demonstrate that 5hmC significantly complements 5mC-based biomarkers in delineating cell identity in both brain and non-brain tissues. Each modification state, including 5hmC alone, accurately discriminates tissue types, enabling high-precision machine learning classification of epigenetic identity. Furthermore, the ternary methylome variations extensively implicate gene transcriptional variation, with age-related changes correlated with gene expression in a tissue-dependent manner. Conclusions Our work reveals how tissue, sex, and age jointly govern the dynamics of the two cytosine modifications, augments the scope of DNA modification biomarker discovery, and provides a reference atlas to explore epigenetic dynamics in development and disease.https://doi.org/10.1186/s13059-025-03808-yDNA methylationHydroxymethylationEpigeneticsMouseCell identityAging |
| spellingShingle | Sol Moe Lee David C. Goldberg Cameron Cloud Jared B. Parker Christopher Krapp Christian E. Loo Elliot Kim Ivan Zhao Chengcheng Jin Rishi Porecha Marisa S. Bartolomei Rahul M. Kohli Wanding Zhou A ternary-code DNA methylome atlas of mouse tissues DNA methylation Hydroxymethylation Epigenetics Mouse Cell identity Aging |
| title | A ternary-code DNA methylome atlas of mouse tissues |
| title_full | A ternary-code DNA methylome atlas of mouse tissues |
| title_fullStr | A ternary-code DNA methylome atlas of mouse tissues |
| title_full_unstemmed | A ternary-code DNA methylome atlas of mouse tissues |
| title_short | A ternary-code DNA methylome atlas of mouse tissues |
| title_sort | ternary code dna methylome atlas of mouse tissues |
| topic | DNA methylation Hydroxymethylation Epigenetics Mouse Cell identity Aging |
| url | https://doi.org/10.1186/s13059-025-03808-y |
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