Structural insights into p300 regulation and acetylation-dependent genome organisation

Ziad Ibrahim, Tao Wang, Olivier Destaing, Nicola Salvi, Naghmeh Hoghoughi, Clovis Chabert, Alexandra Rusu, Jinjun Gao, Leonardo Feletto, Nicolas Reynoird, Thomas Schalch, Yingming Zhao, Martin Blackledge, Saadi Khochbin and Daniel Panne ()
Additional contact information
Ziad Ibrahim: University of Leicester
Tao Wang: CNRS UMR 5309, INSERM U1209, Université Grenoble Alpes, Institute for Advanced Biosciences
Olivier Destaing: CNRS UMR 5309, INSERM U1209, Université Grenoble Alpes, Institute for Advanced Biosciences
Nicola Salvi: Institut de Biologie Structurale, CNRS, CEA, UGA
Naghmeh Hoghoughi: CNRS UMR 5309, INSERM U1209, Université Grenoble Alpes, Institute for Advanced Biosciences
Clovis Chabert: CNRS UMR 5309, INSERM U1209, Université Grenoble Alpes, Institute for Advanced Biosciences
Alexandra Rusu: University of Leicester
Jinjun Gao: The University of Chicago
Leonardo Feletto: University of Leicester
Nicolas Reynoird: CNRS UMR 5309, INSERM U1209, Université Grenoble Alpes, Institute for Advanced Biosciences
Thomas Schalch: University of Leicester
Yingming Zhao: The University of Chicago
Martin Blackledge: Institut de Biologie Structurale, CNRS, CEA, UGA
Saadi Khochbin: CNRS UMR 5309, INSERM U1209, Université Grenoble Alpes, Institute for Advanced Biosciences
Daniel Panne: University of Leicester

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: Abstract Histone modifications are deposited by chromatin modifying enzymes and read out by proteins that recognize the modified state. BRD4-NUT is an oncogenic fusion protein of the acetyl lysine reader BRD4 that binds to the acetylase p300 and enables formation of long-range intra- and interchromosomal interactions. We here examine how acetylation reading and writing enable formation of such interactions. We show that NUT contains an acidic transcriptional activation domain that binds to the TAZ2 domain of p300. We use NMR to investigate the structure of the complex and found that the TAZ2 domain has an autoinhibitory role for p300. NUT-TAZ2 interaction or mutations found in cancer that interfere with autoinhibition by TAZ2 allosterically activate p300. p300 activation results in a self-organizing, acetylation-dependent feed-forward reaction that enables long-range interactions by bromodomain multivalent acetyl-lysine binding. We discuss the implications for chromatin organisation, gene regulation and dysregulation in disease.

Date: 2022
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DOI: 10.1038/s41467-022-35375-2

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