Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency
Abstract Background Metazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Although various genetic and epigenetic signatures have been link...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-07-01
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| Series: | Genome Biology |
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| Online Access: | https://doi.org/10.1186/s13059-021-02424-w |
| _version_ | 1818922573576011776 |
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| author | Yongzheng Li Boxin Xue Mengling Zhang Liwei Zhang Yingping Hou Yizhi Qin Haizhen Long Qian Peter Su Yao Wang Xiaodong Guan Yanyan Jin Yuan Cao Guohong Li Yujie Sun |
| author_facet | Yongzheng Li Boxin Xue Mengling Zhang Liwei Zhang Yingping Hou Yizhi Qin Haizhen Long Qian Peter Su Yao Wang Xiaodong Guan Yanyan Jin Yuan Cao Guohong Li Yujie Sun |
| author_sort | Yongzheng Li |
| collection | DOAJ |
| description | Abstract Background Metazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Although various genetic and epigenetic signatures have been linked to the replication efficiency of origins, there is no consensus on how the selection of origins is determined. Results We apply dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We find that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase. Intriguingly, while both high-efficiency and low-efficiency origins are distributed homogeneously in the TAD during the G1 phase, high-efficiency origins relocate to the TAD periphery before the S phase. Origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observe that the replication machinery protein PCNA forms immobile clusters around TADs at the G1/S transition, explaining why origins at the TAD periphery are preferentially fired. Conclusion Our work reveals a new origin selection mechanism that the replication efficiency of origins is determined by their physical distribution in the chromatin domain, which undergoes a transcription-dependent structural re-organization process. Our model explains the complex links between replication origin efficiency and many genetic and epigenetic signatures that mark active transcription. The coordination between DNA replication, transcription, and chromatin organization inside individual TADs also provides new insights into the biological functions of sub-domain chromatin structural dynamics. |
| first_indexed | 2024-12-20T01:55:41Z |
| format | Article |
| id | doaj.art-29d7ff182c9b43a7a9dfebb40a0c3ba2 |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-20T01:55:41Z |
| publishDate | 2021-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-29d7ff182c9b43a7a9dfebb40a0c3ba22022-12-21T19:57:30ZengBMCGenome Biology1474-760X2021-07-0122112910.1186/s13059-021-02424-wTranscription-coupled structural dynamics of topologically associating domains regulate replication origin efficiencyYongzheng Li0Boxin Xue1Mengling Zhang2Liwei Zhang3Yingping Hou4Yizhi Qin5Haizhen Long6Qian Peter Su7Yao Wang8Xiaodong Guan9Yanyan Jin10Yuan Cao11Guohong Li12Yujie Sun13State Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking UniversityState Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking UniversityState Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking UniversityNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of SciencesPeking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking UniversityState Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking UniversityNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking UniversityState Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking UniversityState Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking UniversityDepartment of Neurobiology, Beijing Centre of Neural Regeneration and Repair, Capital Medical UniversityState Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking UniversityNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of SciencesState Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking UniversityAbstract Background Metazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Although various genetic and epigenetic signatures have been linked to the replication efficiency of origins, there is no consensus on how the selection of origins is determined. Results We apply dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We find that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase. Intriguingly, while both high-efficiency and low-efficiency origins are distributed homogeneously in the TAD during the G1 phase, high-efficiency origins relocate to the TAD periphery before the S phase. Origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observe that the replication machinery protein PCNA forms immobile clusters around TADs at the G1/S transition, explaining why origins at the TAD periphery are preferentially fired. Conclusion Our work reveals a new origin selection mechanism that the replication efficiency of origins is determined by their physical distribution in the chromatin domain, which undergoes a transcription-dependent structural re-organization process. Our model explains the complex links between replication origin efficiency and many genetic and epigenetic signatures that mark active transcription. The coordination between DNA replication, transcription, and chromatin organization inside individual TADs also provides new insights into the biological functions of sub-domain chromatin structural dynamics.https://doi.org/10.1186/s13059-021-02424-wReplication originTopologically associating domain (TAD)Chromatin structureTranscriptionSuper-resolution imagingSTORM |
| spellingShingle | Yongzheng Li Boxin Xue Mengling Zhang Liwei Zhang Yingping Hou Yizhi Qin Haizhen Long Qian Peter Su Yao Wang Xiaodong Guan Yanyan Jin Yuan Cao Guohong Li Yujie Sun Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency Genome Biology Replication origin Topologically associating domain (TAD) Chromatin structure Transcription Super-resolution imaging STORM |
| title | Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency |
| title_full | Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency |
| title_fullStr | Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency |
| title_full_unstemmed | Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency |
| title_short | Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency |
| title_sort | transcription coupled structural dynamics of topologically associating domains regulate replication origin efficiency |
| topic | Replication origin Topologically associating domain (TAD) Chromatin structure Transcription Super-resolution imaging STORM |
| url | https://doi.org/10.1186/s13059-021-02424-w |
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