Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification
Summary: Chromatin and DNA modifications mediate the transcriptional activity of lineage-specifying enhancers, but recent work challenges the dogma that joint chromatin accessibility and DNA demethylation are prerequisites for transcription. To understand this paradox, we established a highly resolv...
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| Language: | English |
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Elsevier
2025-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725004516 |
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| author | Lindsey N. Guerin Timothy J. Scott Jacqueline A. Yap Annelie Johansson Fabio Puddu Tom Charlesworth Yilin Yang Alan J. Simmons Ken S. Lau Rebecca A. Ihrie Emily Hodges |
| author_facet | Lindsey N. Guerin Timothy J. Scott Jacqueline A. Yap Annelie Johansson Fabio Puddu Tom Charlesworth Yilin Yang Alan J. Simmons Ken S. Lau Rebecca A. Ihrie Emily Hodges |
| author_sort | Lindsey N. Guerin |
| collection | DOAJ |
| description | Summary: Chromatin and DNA modifications mediate the transcriptional activity of lineage-specifying enhancers, but recent work challenges the dogma that joint chromatin accessibility and DNA demethylation are prerequisites for transcription. To understand this paradox, we established a highly resolved timeline of their dynamics during neural progenitor cell differentiation. We discovered that, while complete demethylation appears delayed relative to shorter-lived chromatin changes for thousands of enhancers, DNA demethylation actually initiates with 5-hydroxymethylation before appreciable accessibility and transcription factor occupancy is observed. The extended timeline of DNA demethylation creates temporal discordance appearing as heterogeneity in enhancer regulatory states. Few regions ever gain methylation, and resulting enhancer hypomethylation persists long after chromatin activities have dissipated. We demonstrate that the temporal methylation status of CpGs (mC/hmC/C) predicts past, present, and future chromatin accessibility using machine learning models. Thus, chromatin and DNA methylation collaborate on different timescales to shape short- and long-term enhancer regulation during cell fate specification. |
| format | Article |
| id | doaj-art-da9310094aa94ba2b4f727d1f2d88d06 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-da9310094aa94ba2b4f727d1f2d88d062025-08-20T03:52:52ZengElsevierCell Reports2211-12472025-05-0144511568010.1016/j.celrep.2025.115680Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specificationLindsey N. Guerin0Timothy J. Scott1Jacqueline A. Yap2Annelie Johansson3Fabio Puddu4Tom Charlesworth5Yilin Yang6Alan J. Simmons7Ken S. Lau8Rebecca A. Ihrie9Emily Hodges10Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USABiomodal, Chesterford Research Park, Cambridge CB10 1XL, UKBiomodal, Chesterford Research Park, Cambridge CB10 1XL, UKBiomodal, Chesterford Research Park, Cambridge CB10 1XL, UKDepartment of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pediatrics – Section of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Center for Computational Systems Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Corresponding authorSummary: Chromatin and DNA modifications mediate the transcriptional activity of lineage-specifying enhancers, but recent work challenges the dogma that joint chromatin accessibility and DNA demethylation are prerequisites for transcription. To understand this paradox, we established a highly resolved timeline of their dynamics during neural progenitor cell differentiation. We discovered that, while complete demethylation appears delayed relative to shorter-lived chromatin changes for thousands of enhancers, DNA demethylation actually initiates with 5-hydroxymethylation before appreciable accessibility and transcription factor occupancy is observed. The extended timeline of DNA demethylation creates temporal discordance appearing as heterogeneity in enhancer regulatory states. Few regions ever gain methylation, and resulting enhancer hypomethylation persists long after chromatin activities have dissipated. We demonstrate that the temporal methylation status of CpGs (mC/hmC/C) predicts past, present, and future chromatin accessibility using machine learning models. Thus, chromatin and DNA methylation collaborate on different timescales to shape short- and long-term enhancer regulation during cell fate specification.http://www.sciencedirect.com/science/article/pii/S2211124725004516CP: Molecular biologyCP: Developmental biology |
| spellingShingle | Lindsey N. Guerin Timothy J. Scott Jacqueline A. Yap Annelie Johansson Fabio Puddu Tom Charlesworth Yilin Yang Alan J. Simmons Ken S. Lau Rebecca A. Ihrie Emily Hodges Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification Cell Reports CP: Molecular biology CP: Developmental biology |
| title | Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification |
| title_full | Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification |
| title_fullStr | Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification |
| title_full_unstemmed | Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification |
| title_short | Temporally discordant chromatin accessibility and DNA demethylation define short- and long-term enhancer regulation during cell fate specification |
| title_sort | temporally discordant chromatin accessibility and dna demethylation define short and long term enhancer regulation during cell fate specification |
| topic | CP: Molecular biology CP: Developmental biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725004516 |
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