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Chromatin organization drives the search mechanism of nuclear factors

Author

Listed:
  • 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
    Experimental Imaging Center)

  • 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
    IFOM ETS– The AIRC Institute of Molecular Oncology—Via Adamello 16)

  • Carlo Tacchetti

    (Università Vita-Salute San Raffaele
    Experimental Imaging Center)

  • Davide Mazza

    (Università Vita-Salute San Raffaele
    Experimental Imaging Center)

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.

Suggested Citation

  • Matteo Mazzocca & Alessia Loffreda & Emanuele Colombo & Tom Fillot & Daniela Gnani & Paola Falletta & Emanuele Monteleone & Serena Capozi & Edouard Bertrand & Gaelle Legube & Zeno Lavagnino & Carlo Ta, 2023. "Chromatin organization drives the search mechanism of nuclear factors," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42133-5
    DOI: 10.1038/s41467-023-42133-5
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    References listed on IDEAS

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    1. Yukti Hari-Gupta & Natalia Fili & Ália dos Santos & Alexander W. Cook & Rosemarie E. Gough & Hannah C. W. Reed & Lin Wang & Jesse Aaron & Tomas Venit & Eric Wait & Andreas Grosse-Berkenbusch & J. Chri, 2022. "Myosin VI regulates the spatial organisation of mammalian transcription initiation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Davide Normanno & Lydia Boudarène & Claire Dugast-Darzacq & Jiji Chen & Christian Richter & Florence Proux & Olivier Bénichou & Raphaël Voituriez & Xavier Darzacq & Maxime Dahan, 2015. "Probing the target search of DNA-binding proteins in mammalian cells using TetR as model searcher," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    3. Ruggero Cortini & Guillaume J. Filion, 2018. "Theoretical principles of transcription factor traffic on folded chromatin," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    4. Tatsuya Morisaki & Waltraud G. Müller & Nicole Golob & Davide Mazza & James G. McNally, 2014. "Single-molecule analysis of transcription factor binding at transcription sites in live cells," Nature Communications, Nature, vol. 5(1), pages 1-8, December.
    5. Alessia Loffreda & Emanuela Jacchetti & Sofia Antunes & Paolo Rainone & Tiziana Daniele & Tatsuya Morisaki & Marco E. Bianchi & Carlo Tacchetti & Davide Mazza, 2017. "Live-cell p53 single-molecule binding is modulated by C-terminal acetylation and correlates with transcriptional activity," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
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    Cited by:

    1. Timothy A. Daugird & Yu Shi & Katie L. Holland & Hosein Rostamian & Zhe Liu & Luke D. Lavis & Joseph Rodriguez & Brian D. Strahl & Wesley R. Legant, 2024. "Correlative single molecule lattice light sheet imaging reveals the dynamic relationship between nucleosomes and the local chromatin environment," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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