p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response
Abstract Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architectu...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46666-1 |
| _version_ | 1827291428881956864 |
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| author | François Serra Andrea Nieto-Aliseda Lucía Fanlo-Escudero Llorenç Rovirosa Mónica Cabrera-Pasadas Aleksey Lazarenkov Blanca Urmeneta Alvaro Alcalde-Merino Emanuele M. Nola Andrei L. Okorokov Peter Fraser Mariona Graupera Sandra D. Castillo Jose L. Sardina Alfonso Valencia Biola M. Javierre |
| author_facet | François Serra Andrea Nieto-Aliseda Lucía Fanlo-Escudero Llorenç Rovirosa Mónica Cabrera-Pasadas Aleksey Lazarenkov Blanca Urmeneta Alvaro Alcalde-Merino Emanuele M. Nola Andrei L. Okorokov Peter Fraser Mariona Graupera Sandra D. Castillo Jose L. Sardina Alfonso Valencia Biola M. Javierre |
| author_sort | François Serra |
| collection | DOAJ |
| description | Abstract Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies. |
| first_indexed | 2024-04-24T12:37:58Z |
| format | Article |
| id | doaj.art-0a358ee1ea5c43e4a2c5658e8409ffd6 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T12:37:58Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-0a358ee1ea5c43e4a2c5658e8409ffd62024-04-07T11:24:00ZengNature PortfolioNature Communications2041-17232024-04-0115111910.1038/s41467-024-46666-1p53 rapidly restructures 3D chromatin organization to trigger a transcriptional responseFrançois Serra0Andrea Nieto-Aliseda1Lucía Fanlo-Escudero2Llorenç Rovirosa3Mónica Cabrera-Pasadas4Aleksey Lazarenkov5Blanca Urmeneta6Alvaro Alcalde-Merino7Emanuele M. Nola8Andrei L. Okorokov9Peter Fraser10Mariona Graupera11Sandra D. Castillo12Jose L. Sardina13Alfonso Valencia14Biola M. Javierre15Josep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteWolfson Institute for Biomedical Research, University College LondonDepartment of Biological Science, Florida State UniversityJosep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteJosep Carreras Leukaemia Research InstituteBarcelona Supercomputing CenterJosep Carreras Leukaemia Research InstituteAbstract Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.https://doi.org/10.1038/s41467-024-46666-1 |
| spellingShingle | François Serra Andrea Nieto-Aliseda Lucía Fanlo-Escudero Llorenç Rovirosa Mónica Cabrera-Pasadas Aleksey Lazarenkov Blanca Urmeneta Alvaro Alcalde-Merino Emanuele M. Nola Andrei L. Okorokov Peter Fraser Mariona Graupera Sandra D. Castillo Jose L. Sardina Alfonso Valencia Biola M. Javierre p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response Nature Communications |
| title | p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response |
| title_full | p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response |
| title_fullStr | p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response |
| title_full_unstemmed | p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response |
| title_short | p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response |
| title_sort | p53 rapidly restructures 3d chromatin organization to trigger a transcriptional response |
| url | https://doi.org/10.1038/s41467-024-46666-1 |
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