Chromatin organization drives the search mechanism of nuclear factors

Matteo Mazzocca, Alessia Loffreda, Emanuele Colombo, Tom Fillot, Daniela Gnani, Paola Falletta, Emanuele Monteleone, Serena Capozi, Edouard Bertrand, Gaelle Legube, Zeno Lavagnino, Carlo Tacchetti and Davide Mazza ()
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Matteo Mazzocca: Università Vita-Salute San Raffaele
Alessia Loffreda: Experimental Imaging Center
Emanuele Colombo: Università Vita-Salute San Raffaele
Tom Fillot: Università Vita-Salute San Raffaele
Daniela Gnani: Università Vita-Salute San Raffaele
Paola Falletta: Università Vita-Salute San Raffaele
Emanuele Monteleone: Università Vita-Salute San Raffaele
Serena Capozi: Institut de Génétique Moléculaire de Montpellier, CNRS
Edouard Bertrand: Institut de Génétique Moléculaire de Montpellier, CNRS
Gaelle Legube: CNRS, Université de Toulouse, UT3
Zeno Lavagnino: Experimental Imaging Center
Carlo Tacchetti: Università Vita-Salute San Raffaele
Davide Mazza: Università Vita-Salute San Raffaele

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Nuclear factors rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple factors explore chromatin, combining live-cell single-molecule tracking with multifocal structured illumination of DNA density. We find that factors displaying higher bound fractions sample DNA-dense regions more exhaustively. Focusing on the tumor-suppressor p53, we demonstrate that it searches for targets by alternating between rapid diffusion in the interchromatin compartment and compact sampling of chromatin dense regions. Efficient targeting requires balanced interactions with chromatin: fusing p53 with an exogenous intrinsically disordered region potentiates p53-mediated target gene activation at low concentrations, but leads to condensates at higher levels, derailing its search and downregulating transcription. Our findings highlight the role of disordered regions on factors search and showcase a powerful method to generate traffic maps of the eukaryotic nucleus to dissect how its organization guides nuclear factors action.

Date: 2023
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DOI: 10.1038/s41467-023-42133-5

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