p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response

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 and Biola M. Javierre ()
Additional contact information
François Serra: Josep Carreras Leukaemia Research Institute
Andrea Nieto-Aliseda: Josep Carreras Leukaemia Research Institute
Lucía Fanlo-Escudero: Josep Carreras Leukaemia Research Institute
Llorenç Rovirosa: Josep Carreras Leukaemia Research Institute
Mónica Cabrera-Pasadas: Josep Carreras Leukaemia Research Institute
Aleksey Lazarenkov: Josep Carreras Leukaemia Research Institute
Blanca Urmeneta: Josep Carreras Leukaemia Research Institute
Alvaro Alcalde-Merino: Josep Carreras Leukaemia Research Institute
Emanuele M. Nola: Josep Carreras Leukaemia Research Institute
Andrei L. Okorokov: University College London
Peter Fraser: Florida State University
Mariona Graupera: Josep Carreras Leukaemia Research Institute
Sandra D. Castillo: Josep Carreras Leukaemia Research Institute
Jose L. Sardina: Josep Carreras Leukaemia Research Institute
Alfonso Valencia: Barcelona Supercomputing Center
Biola M. Javierre: Josep Carreras Leukaemia Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46666-1

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